Stem Cell Program Blog

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Welcome to our Student-Authored Stem Cell Research BlogMA Blog Intro

Master's students in our Stem Cell Program perform cutting edge translational research in the field of regenerative medicine. The intention of this site is to provide a platform for our graduate students to describe their research to the greater community. In some cases, students chose instead to write editorials aimed at providing a general understanding of stem cell research. In all cases, students attempted to describe research in a way that would be consumable and informative - and possibly even entertaining - to all readers.

To protect the confidentiality of unpublished research currently underway at UC Davis, the specific names of genes, proteins, cells, and tissue types have often been replaced with aliases or referred to generically (e.g., "factor X" or "a specific peptide"), unless the information is already publicly available elsewhere.

If you have questions or comments, please contact the site editor: Dr. Kimberly Mulligan (kimberly.mulligan@csus.edu)

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Table of Contents

Spring 2017

  1. What Skin Cells Can Tell Us About Huntington’s Disease - By Jasmine Carter
  2. Oblivion is Dangerous: Induced Pluripotent Stem Cells and Predictive Toxicology - By Sakereh Carter
  3. The Revolution in Personalized Medicine - By Elizabeth Cortez-Toledo
  4. Superman vs. Doomsday: The Battle of Cancer and its Stem Cells - By Deidra Gordon
  5. Model Medicine - By Bruce Hammerstad
  6. Stem Cells 101: From Stem Cells to Specialized Cells - By Clayton Lin (coming soon)
  7. Care Packages to the Rescue! - By Jennifer Phan (coming soon)
  8. Stem Cell Therapy for Your Brain - By Jacqueline Silva (coming soon)
  9. Using the Body’s Own Natural Defenses to Better Fight Cancer - By Ian Sturgill (coming soon)

Spring 2016

Student Research

  1. A Cure For Osteoarthritis: Next Generation Mesenchymal Stem Cells - By Andrew Cicchetto
  2. Stem Cell Therapy from your Furry Friends to you! - By Kaitlin Clark
  3. Growing Liver Organs to Save Lives - By Dane Coleal-Bergum
  4. A Step Closer To Curing Multiple Sclerosis - By Christopher Croteau
  5. Stem Cell Attachment and the Unpredictable Nature of Science - By Hannah Fox
  6. A Promising Future: An Alternative to Electronic Pacemakers - By Hillary Kao
  7. Breath of Fresh Air: Regenerative Medicine Bringing Hope to Patients Needing New Airways - By Josh Martinez
  8. Paramedic Activity of MSCs Utilized in Tunable Hydrogel for Chronic Wound Treatment - By Nora Rimpo
  9. Specific Histone Gene may be a Key Player in Brain Development - By Allison Wagner
  10. Looking for a Cure to Spina Bifida using Different Mesenchymal Stem Cell Sources - By Scott Walker

Editorials

  1. What is an Induced Pluripotent Stem Cell? - By Vanessa Aguilar
  2. The Bioethics of Embryonic Stem Cell Research - By Clement Aroh
  3. Differentiating Embryonic and Induced Pluripotent Stem Cells - By Nathan Haigh
  4. The Challenges and Benefits of Using Stem Cells in Psychiatry - By Jessica Palka

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Student-Authored Blogs

Spring 2017

What Skin Cells Can Tell Us About Huntington’s Disease 

jasmine carterBy Jasmine Carter

In the United States, 30,000 individuals currently suffer from Huntington’s disease (HD), a neurodegenerative disease that is always lethal and causes death 15-20 years after diagnosis [1] [2] [3]. HD causes uncontrolled movements, cognitive impairment, and emotional problems [4]. Diagnosis typically occurs either in adulthood or childhood, depending on the type of genetic mutation involved [4]. Currently, treatments are limited and there is no cure.

But what if the key to treating HD could be found in the cells of our body?

Emerging research suggests that cells found in the dermis of our skin may have therapeutic potential for this devastating condition [5]. The specific cells are called fibroblasts and they normally function to make proteins like collagen, which give skin its elastic nature [6]. Unlike most cells, fibroblasts are unusually easy to grow in a petri dish in the lab, making them an ideal research tool.skin diagram

But how can fibroblasts help with a brain disease? Huntington’s disease is caused by a genetic mutation of a gene that is required in neurons; when this mutation is present it ultimately causes neurons to die [ 4]. It turns out that the fibroblasts in the dermis of a person with HD will carry the exact same genetic mutation. Therefore, by studying the fibroblasts from HD patients we can perhaps dissect the molecular mechanism of the HD mutation to learn how it destroys neurons. In addition to being easily grown in the lab, the ability of fibroblasts to model genetic mutations is another advantage of using these cells in research.

One way scientists are studying fibroblasts from HD patients involves the use of gene-editing techniques. Such techniques allow researchers to edit genes in different ways, most commonly by removing a gene altogether, changing its genetic sequence, or by turning it on. In the case of HD, gene-editing tools have been used to turn off the mutated gene in order to assess if limiting the function of the mutant gene in fibroblasts is possible [4].

Some gene-editing tools can be used to facilitate reprogramming of patient-derived fibroblasts to induced pluripotent stem cells (iPSCs), a type of artificially created stem cell that resembles embryonic stem cells [7]. These iPSCs can tell us a lot about disease pathology; there are established methods for inducing iPSCs to form neurons—meaning fibroblasts taken from a skin sample of an HD patient can ultimately show scientists how HD neurons are impaired [5]. This is a major advantage given that skin cells are easily obtained, whereas brain tissue from a live patient is obviously not. And because that fibroblast has the HD gene, the iPSCs and induced neurons will have it, too.

These induced neurons are similar to the neurons dying in HD patients. Therefore, induced neurons can help scientists develop treatments that will improve HD patient health. Treatments given to a HD patient should not put their neurons at additional risk, which makes knowing how a drug will affect neurons important. Studying the induced neurons’ response to varying types and amounts of drugs, can help scientists determine if a drug is toxic and likely to kill the neurons in a HD patient’s body. Using induced neurons to advance treatment options does not have to be limited to drug testing outside the body, as these cells can potentially be a therapy injected back into the patient [5].

When a patient’s own induced neurons are administered as a therapy it decreases the likelihood of death by host-graft rejection. Host-graft rejection occurs when the host’s immune system has recognized the donor’s cells as foreign invaders, which can lead to severe inflammation and prevent the body from working properly. Preventative measures for host-graft rejection are immunosuppressant drugs that leave the host more susceptible to life-threatening infections [7]. If induced neurons are injected into a HD patient, an immune response is less likely to occur because the induced neurons are not foreign invaders to the immune system.

Our body is programmed to defend itself against diseases. However, our body is not always successful in doing so when the disease is caused by a genetic mutation. It is truly remarkable that scientists can use skin cells themselves and ones reprogrammed to induced neurons to advance understanding on HD and develop treatments for patients with Huntington’s disease.

References

  1. Ross, C.A., Tabrizi, S.J. (2011). Huntington’s disease: from molecular pathogenesis to clinical treatment. Lancet Neurology, Vol. 10, pp. 83-98.
  2. Walker, F. (2007). Huntington’s disease. The Lancet, Vol. 269, pp. 218-228.
  3. Huntington’s Disease Statistics. (2017) MEDTV Health Information Brought to Life, Retrieved from http://nervous-system.emedtv.com/huntington's-disease/huntington's-disease-statistics.html
  4. Fink, K.D., Deng, P., Gutierrez, J., Anderson, J.S., Torrest, A., Komarla, A., Nolta, J.A. (2016). Allele-Specific Reduction of the Mutant Huntingtin Allele Using Transcription Activator-Like Effectors in Human Huntington’s Disease Fibroblasts. Cell Transplantation, Vol. 25, pp. 677-686.
  5. An, M.C., Zhang, N., Scott, G., Montoro, D., Wittkop, T., Mooney, S., … Ellerby, L.M. (2012). Genetic Correction of Huntington’s Disease Phenotypes in Induced Pluripotent Stem Cells. Cell Stem Cell, Vol. 11, pp. 253-263.
  6. Mandal, M. (2014, September 23). What are Fibroblasts? Retrieved from: News Medical Life Sciences.
  7. Takahashi, K., Yamanaka S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, Vol. 126, pp. 663-676.
  8. About Immunosuppressant Drugs. (2016). Healthline, Retrieved from http://www.healthline.com/health/immunosuppressant-drugs#Introduction1)

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Oblivion is Dangerous: Induced Pluripotent Stem Cells and Predictive Toxicology

sakereh carterBy Sakereh Carter

Picture this: You grab an apple in the morning for breakfast, say goodbye to your loved one, and jump into your car to drive to the gas station. Pretty harmless morning, right? Maybe, on the surface, but in reality the apple you ate for breakfast contains Thiabendazole, a common pesticide residue on apples known to cause cancer and reproductive toxicity (Pesticide Action Network, 2010). The gasoline used to fill up your car contains several hazardous chemicals known to cause cancer, such as benzene. At the gas station, diesel emissions bombarded your respiratory system increasing your susceptibility to cancer. In fact, the California Air Resources Board estimated that 70% of all cancer related illnesses in California arise from exposure to diesel emissions (California Air Resources Board, 2017).

We are exposed to a vast number of environmental toxicants everyday. In 2015 alone, 2.9 billion pounds of toxicants were released into air, water, and land sources. (Environmental Protection Agency, 2017). Globally, approximately 12.6 million deaths are attributed to environmental toxicant exposure each year (World Health Organization, 2016). Toxins are substances that are harmful to the human body. Environmental toxicants are toxic substances introduced into the environment. When toxins enter cells they can disrupt essential cellular processes, such as chemical reactions, cell division, and cell survival. This causes cellular dysfunction and can lead to organ toxicity and various diseases, including cancer. To prevent toxicant-associated disorders, we need efficient ways to test how chemicals might affect the human body before they are released into the environment.sakereh figure

Interestingly, researchers are now using stem cells to test the effects of environmental toxicants. Stem cells are naturally occurring cells that have the ability to divide and become different specialized cell types within the body. Specialized cell types are cells that perform a specific function. Stem cells have two important functions during adult life: 1) replenishing the stem cell population, and 2) replacing damaged, aging, or dead cells when necessary. For example, hepatocytes detoxify harmful substances in the liver. The process of a stem cell producing a specialized cell type is termed differentiation. There are several different stem cells used to research environmental toxicants; however, induced pluripotent stem cells (iPSCs) may offer the best approach to toxicological testing.

iPSCs are a great choice for toxicity testing because of their versatility and accessibility. For example, iPSCs have the ability to differentiate into all 200 specialized cell types in the body. Therefore, a researcher can study toxicity in several different cell types. Furthermore, iPSCs are easily created by taking skin cells from a human individual and converting them into stem cells in a petri dish! Most importantly, utilizing iPSCs allows researchers to observe potential toxic effects in human cells before examining toxicity at the organismal level.

There are several ways to test the effects of environmental toxicants in iPSCs. For example, stem cell populations may be examined for changes in metabolism, cellular toxicity, and appearance following exposure to environmental toxicants. Additionally, stem cell populations may be monitored for their differentiation potential in the presence of toxic substances. In fact, a study performed by Ceccatelli et. al 2013 found that, when exposed to the neurotoxin methyl mercury, neural stem cells displayed decreased ability to divide and differentiate into neurons. Researchers may also examine toxin-mediated changes in gene expression and protein levels within a cell. Notably, scientists can also test multiple toxins at once, which is more reflective of a real world scenario; you are likely simultaneously exposed to a number of toxins on a daily basis (depending on where you live). It’s also possible to test the effects of beneficial substances—like vitamins—to examine their ability to suppress or abolish symptoms associated with toxicity.

The use of stem cells for predictive toxicology has become more commonplace in the field of research, and their application for human toxicity modeling is limitless. Ultimately, iPSCs offer a promising solution to toxicity screening in several ways getting us one step closer to understanding the biological underpinnings of toxicity. As you can see, iPSCs pave the way for enhanced toxicological testing!


References

"An estimated 12.6 million deaths each year are attributable to unhealthy environments." World Health Organization. World Health Organization, n.d. Web. 10 Mar. 2017.        

Ceccatelli, S., et al. "Long-Lasting Neurotoxic Effects of Exposure to Methylmercury During Development." Journal of Internal Medicine 273.5 (2013): 490-97. Print.

Network, Pesticide Action. "What’s On My Food :: Pesticides on Apples." What’s On My Food :: Pesticides on Apples. N.p., 2010. Web. 10 Mar. 2017.

"Overview: Diesel Exhaust and Health." California Environmental Protection Agency Air Resources Board. N.p., n.d. Web. 10 Mar. 2017.

TRI National Analysis 2014. Washington, D.C.: U.S. Environmental Protection Agency, Pollution Prevention and Waste Management, 2016. Print.

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The Revolution in Personalized Medicine

ElizabethBy Elizabeth Cortez-Toledo

What if I told you that scientists are one step away from finding a therapeutic treatment for various diseases, including those that were once thought to be incurable? It seems a little far-fetched doesn’t it? Well as unbelievable as it sounds, scientists have discovered techniques that will enable delivery of personalized treatment to patients suffering from a wide range of diseases. In the past few years, there has been a major breakthrough in the field of regenerative medicine, a field of translational medicine centered on the use of stem cells to regenerate tissues and organs. You’ve probably heard that stem cells have the ability to become any type of cell in the body. They regenerate damaged tissues and deliver therapeutic molecules. It’s quite impressive! I’m sure you’ve asked yourself: how do stem cells become specialized cells? What properties allow them to deliver specific molecules? And, lastly, what are the benefits associated with the use of stem cells?

Let us begin our journey of personalized medicine by talking about induced pluripotent stem cells (iPSCs). These revolutionary cells can be generated from any mature cell found in the body, like a skin cell. iPSCs are called “induced” pluripotent stem cells because scientists “induce” these cells to become stem cells by adding a few key genes to them. The term “pluripotent” refers to their ability to create any cell type in the body. That means scientists can generate any type of cell from a patient’s own cells! (Figure 1) Why is this important, you ask? Well, if docs were to use patient-derived iPSCs to create an organ to put back into the patient it would eliminate the risk that the patient’s immune system would attack and destroy the transplanted cells (this is the biggest danger of organ transplantation). Therefore, iPSC-derived cells can survive long-term and provide the therapeutic benefits for which they were engineered .

But let’s take a step back. During the beginning stages of human development, an embryo begins as a mass of pluripotent stem cells that require specific signals to become the different cell types needed to form an organism. The different signals provided to the immature cells allow certain genes to be turned on or off, depending on the tissue or organ the cell is destined to become. Just like in embryonic development, scientists can mimic the signals that dictate the fate of each cell in vitro, outside the human body. Using combinations of different molecules, scientists can now restrict the cell to become the specific cell they desire. For example, individuals suffering from Hemophilia A, a genetic deficiency in blood clotting, lack a single but critical protein known as Factor 8 that allows their blood to clot following an injury. If scientists can generate the cells specific to the organ or tissue responsible for expressing this protein, they can then genetically manipulate the cells and restore the body’s own ability to produce Factor 8, and therefore eliminate the need for life-long treatment. That’s right! Stem cells may be used to rescue Factor 8 and thus cure Hemophilia A! Unfortunately, the process is not as easy as it sounds.

Let’s look at the molecular level of this disorder. Factor 8 is mainly released by endothelial and hepatocyte cells. Endothelial cells are the cells that line the interior of blood vessels, while hepatocyte cells are the main cells that make up the liver. Current research is focusing on generating endothelial and hepatocyte cells from patient-derived iPSCs to treat Hemophilia A. If iPSCs are successfully differentiated into endothelial and hepatocyte cells; these cells can be genetically manipulated to express Factor 8. How exactly does this work? Viruses! Harmless viruses are engineered to carry the gene responsible for making the protein of interest. The iPSCs or differentiated cells are then exposed to these viruses that maintain the ability to deliver the foreign DNA, where it integrates into the host’s DNA, without causing harm (Figure 2). It might sound like a scary technique, but so far it is one of the most efficient ways of delivering specific molecules to our cells.

This research is being performed at the Institute of Regenerative Cures by scientist Dr. Ping Zhou and her team. They have demonstrated successful differentiation of iPSCs into endothelial and hepatocyte cells by exposing them to specific molecules that are needed to guide them down their appropriate cell lineage. The differentiated cells demonstrate markers specific to both cell types, confirming the identity of the desired cells. Even more exciting, Factor 8 was successfully expressed in these cells with the help of viruses carrying the Factor 8 gene. Expression of Factor 8 in these cells was at higher levels compared to non-virus exposed cells and human umbilical vein endothelial cells (HUVECs), which are obtained from biopsied tissue and represent normal biological levels of Factor 8.

The technique described above allows expression of Factor 8 in vitro, with hopes that once these cells are transplanted back into the patient, the cells will express and release the protein at levels comparable to those that are naturally present in a healthy individual (Figure 3). Although further research is needed to accomplish clinical trials, this practice has so far proven an attainable personalized gene therapy to cure Hemophilia A.

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Superman vs. Doomsday: the Battle of Cancer and its Stem Cells

deidra gordonBy Deidra Gordon

Tumors are like the bad guys from a comic, taking over tissue and organs in our bodies, attacking and destroying them. Most tumors are heterogeneous, meaning they consist of multiple cell types. One cell type within a tumor is known as the cancer stem cell (CSC), which can be compared to a super villain from a comic, such as Doomsday. The second type are the normal tumor cells which are similar to the regular bad guys, that can be targeted and destroyed by current chemotherapeutics, much like bad guys getting captured by police officers. Since chemotherapeutics are only effective on rapidly dividing cells, such as normal tumor cells and unfortunately some healthy cells, they do not target CSCs. Similar to comic books, chemotherapeutics cannot defeat the super villain, which leaves Doomsday free to cause all types of mayhem.   This is alarming because even when all normal tumor cells are eradicated, CSCs may persist leading to metastasis and recurrence due to their stem cell capabilities, such as self-renewal (Fig.1). Thus, we need to develop a method to target not only the tumor cells, but also the CSCs within the tumor population without affecting the normal, healthy cells. We need a superhero to come save the day. Scientists are currently working to develop an efficient strategy to target both CSCs and tumor cells through interactions with a type of protein called an integrin. Integrins are like “The Daily Planet” for our cells, a source of communication. The ability of integrins to participate in cell signaling can affect tumor progression and metastasis. Studies of a specific integrin, Alpha v beta 6 (αvβ6), have shown that it is a useful target of tumor cells and CSCs because αvβ6 is present in high amounts on the surface of cancerous cells whereas very low amounts are found on normal cells [1]. These expression levels allow for delivery of chemotherapeutics to only the cancerous cells without affecting normal, healthy cells.

In order to target cancer cells overexpressing αvβ6 integrins, we need to develop a peptide that can target and bind to αvβ6. A previous study identified a peptide that contained two specific amino acid sequences that are important contributors to the binding of αvβ6 [2]. Using the two amino acid sequences previously identified, we can synthesize a peptide library using a method called the One-Bead-One-Compound (OBOC) library method. This approach allows for production of millions of different peptides, so we can identify the ideal amino acid sequence that will give us the best targeting ability and act as our Superman, the only one strong enough to defeat Doomsday and keep the innocent bystanders safe.

Not only will this method decrease the current side effects of current chemotherapeutic treatments due to their inability to target only tumor cells, but it will also decrease the possibility of metastasis and recurrence by specifically targeting the CSC population. If we are lucky, our molecular superman will save the day and rid the city of the evil villain, Doomsday.

References

  1. Bandyopadhyay A, Raghavan S. Defining the role of integrin αvβ6 in cancer. Current drug targets. 2009;10(7):645.
  2. Liu H, Wu Y, Wang F, Liu Z. Molecular imaging of integrin αvβ6 expression in living subjects. American journal of nuclear medicine and molecular imaging. 2014;4(4):333.

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Model Medicine

Bruce HammerstadBy Bruce Hammerstad

There are many kinds of models in the world. There are model airplanes, model cars, even supermodels! Ok, nevermind the supermodels and model cars, they’re not the reason we’re here today. We’re here to talk about disease models.   So, what is a disease model? Generally it is an animal—perhaps a rat—that has some abnormality that mimics the pathology of a human disease. But before we continue to discuss disease models, I would like to return to the toy models and talk about the qualities that make any particular model a good model.

Imagine a toy jet fighter that a child is playing with, pretending to fly at the dinner table as their hand passes over their plate, which is actually a fortified enemy installation made of vegetables. As it passes over, the pilot launches 200 nuclear missiles, demolishing the broccolHammerstad1i! Yay! Time for dessert!

Now wait a minute, can a single jet really launch 200 missiles?   Not likely. That isn’t an accurate representation of the real thing. Does that mean it’s not a good model? That depends on its purpose. The purpose of this particular model is to stimulate the imagination of a bored kid. Job well done! But what if the purpose of was to test aerodynamics? We would need a model that behaves similarly to the real thing, so this particular model wouldn’t be well suited for testing aerodynamics.

Ok, so we know that whether or not a model is good depends two things: its purpose, and how accurately it mimics what is being tested. What does that mean in terms of an animal model of disease? It means we would need the disease pathology in the animal to behave similarly to how it does in humans. Fortunately, because of our close relatedness to other life on Earth, many diseases do. You’ve probably heard of both dogs and people having cancer, a disease that threatens our mortality every bit as much as it threatens any other animal. This is because we share similar essential processes of life. Errors in DNA replication can happen in dogs just like it can happen in us. This fact is fundamental to how medical science is advanced. There is, however, an important issue—just because we are similar doesn’t mean we aren’t different. mouse

Consider the jet fighter. A key difference between a jet that we design and build from the ground up and an animal disease model is the understanding of how the thing works. The engineers that designed the jet have an excellent understanding of how each moving part within their creation works, after all…they made it! Research scientists, on the other hand, didn’t design the rat, and there remains a great deal to learn about the processes of life. So, if there is such a gap in knowledge, how can research into disease modeling even work? It works because it is the best available model, but we know it’s not perfect.

It is very important that we recognize the differences and unknowns between us and our disease models. We must continue to improve our understanding of disease pathologies so that we may cure those diseases, but we must also bear in mind the differences between our models and us. It may be the difference between life and death!

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Spring 2016

Research

A Cure For Osteoarthritis: Next Generation Mesenchymal Stem Cells

Andy CicchettoBy Andrew Cicchetto

Sadly, the odds are not in your favor. Data indicates that once you turn 65 you have more than a 60% chance of developing osteoarthritis (OA)1. If you are already over 65, I imagine you are likely nodding your head in unfortunate agreement.

OA is a debilitating disease that causes joint pain brought on by chronic inflammation and cartilage degeneration that worsens with time. People suffering from OA deal with pain on a regular basis. Can you imagine simple tasks like walking the dog or grocery shopping being dreaded, painful undertakings? Or a more extreme example: can you imagine not being able to run to safety in the event of an emergency? You should not be shrugging your shoulders in apathy at these examples; remember that you and your loved one have a greater than 1 in 2 chance of being faced with these scenarios later in life. Something must be done about this devastating, painful disease.

So what’s the cure? It seems that for such a pervasive disease, surely there would be some medical remedy. Unfortunately, the only treatment options currently available are pain medications or, in more severe cases, surgical replacement of the arthritic joint.

However, exciting new research indicates mesenchymal stem cells (MSCs) may be the answer to treating OA. These incredible cells have been termed the paramedics of the body for their ability to modulate the immune system and regenerate damaged tissue, which are two prominent targets of OA. MSCs produce a variety of molecules to activate the body’s own healing machinery. In some cases, MSCs permanently engraft in the patient and differentiate (i.e., develop) into bone or cartilage thereby replacing lost tissue. Significantly, clinical trials of MSCs have shown their unwavering safety; there have been no deleterious consequences of MSC transplantation into human patients2. However, effectiveness of MSCs has been inconsistent across human studies, likely due to the inherent variability of living cells. MSC schematic

To solve the variability problem, modified (and unharmful) viruses have been used to deliver genes of therapeutic interest into MSCs. Viruses have naturally evolved to put genetic information into host cells (usually causing disease), but now we have learned how to use them to put beneficial DNA into the host genome (instead of disease-causing DNA). This, in essence, allows the recipient cells (MSCs) to produce medication in a reliable fashion.

We used this virus-delivery mechanism to supply MSCs with genes coding for important reparative factors to increase MSC therapeutic potency. These superior Next Generation MSCs, as scientists are calling them, represent a cutting-edge combined cell and gene therapy platform that is showing promise as an OA treatment option.

But not so fast! Genetic manipulation of MSCs requires additional studies to ensure their acclaimed safety profile is retained post-modification. When viruses deliver genes to cells, they insert the genes at random locations in the host cell DNA. If this random gene insertion was to occur in the middle of another important gene within the MSC DNA, it could have dire consequences. It turns out the odds of this happening are very low, but we must be comprehensive in our testing to ensure MSCs meant for improving health do not do the opposite. Therefore, a battery of experiments have been conducted to demonstrate that the MSCs are still behaving normally (aside from the intended changes).

Our experiments evaluating MSC growth, shape and size show that the cells appear and function as expected. We have also measured the level of therapeutic gene expression, much like gauging the dose of medicine needed to treat a disease. This assessment will allow for a calculated drug delivery system when using our Next Generation MSCs to treat OA.

We have also used functional experiments that have validated the exaggerated immune suppression capabilities of Next Generation MSCs - an important aspect of OA treatment. White blood cells (the same ones that cause OA) were limited in their ability to grow and promote inflammation. The genes inserted into MSCs by the virus were responsible for accomplishing this task; unmodified MSCs were much less effective. 

Next, we investigated the ability of Next Generation MSCs to make cartilage. It seems that the genetic modification does in fact help MSCs turn into cartilage! Production of new cartilage could help rebuild the cartilage that has been lost in OA patients.

Could it be that Next Generation MSCs are the answer to one of the world’s most prominent musculoskeletal diseases? We will find out once this technology moves to first-in-human clinical trials. Stay tuned.

References

  1. Lawrence, R. C., Felson, D. T., Helmick, C. G., Arnold, L. M., Choi, H., Deyo, R. A.National Arthritis Data, W. (2008). Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum, 58(1), 26-35. doi: 10.1002/art.23176
  2. Barry, F., & Murphy, M. (2013). Mesenchymal stem cells in joint disease and repair. Nat Rev Rheumatol, 9(10), 584-594. doi: 10.1038/nrrheum.2013.109

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Stem Cell Therapy from your Furry Friends to you!

Kaitlin ClarkBy Kaitlin Clark

Stem cell therapy has gone to the animals! Did you know that at the UC Davis Veterinary Medicine Teaching Hospital (VMTH) there is currently a clinical regenerative medicine laboratory (RML) that can provide stem cell therapy to your beloved pet? The UC Davis RML is one of the only academic institutions in the nation to provide clinical veterinary stem cell services.

The RML opened its doors in 2007. Initially only treating horses, the lab has grown immensely in the past few years and is now also catering to dogs and cats. Stem cell therapy has proven to be a great therapeutic option for many diseases that affect all types of animal patients. 

The potential benefits of veterinary stem cell therapy does not only serve our furry cliental. Horses, cats, dogs and many other animals serve as great model organisms for human diseases. You may have heard of scientists using mouse models in their laboratories to mimic human diseases. But large animals are considered to be superior models because they suffer from naturally occurring diseases that are similar to humans. For instance, sport horses frequently suffer from cartilage, ligament and bone injuries that resemble injuries common to human athletes. Instead of creating an artificial injury in mice, we can use animal patients that naturally suffer from any particular injury or disease. In addition, large animals are often more genetically similar to us than mice or lower vertebrates, so these animal patients serve as better examples for new therapies that might eventually be used later down the line for humans. Horse

At the UC Davis veterinary clinic, we use adult derived mesenchymal stem cells (MSCs) as a form of stem cell therapy to treat horses. One great feature of MSC- based therapies is that we can use a patient’s own stem cells to treat them! This makes it less likely that the animal’s immune system would react to a cell-based therapy – because the cell-based therapy would be completely composed of that animal’s own cells. In addition, MSCs can be isolated with minimal invasiveness from bone marrow, fat or umbilical cord blood, and tissue.

Let’s use an example. Imagine a horse comes into the clinic with a ligament injury. Veterinarians could collect a small piece of fat for MSC isolation. That fat would take about two weeks to be processed and viola! MSCs would be ready to inject into that patient’s injury site to promote healing of the ligament.

So now you know we can use MSCs for clinical applications in a horse, but what do we know about how these stem cells work? In the laboratory of Dr. Dori Borjesson we found that MSCs collected from different tissues in horses have the ability to inhibit inflammation. The inhibition of inflammation can promote healing in damaged tissues. But we want to understand how the MSCs work to suppress inflammation. We have examined a host of inflammatory proteins (molecules that cause inflammation) and are just starting to uncover the mechanism by which horse MSCs work their magic.  The short answer [for now] is that for everything we do know, there is still a lot we have yet to learn.  So MSC research presses on!

But now you may ask yourself, what is the benefit of using stem cells as opposed to some other type of anti-inflammatory drug like aspirin? The answer to this is regeneration! Regeneration refers to the process of re-growing tissue that has been lost or damaged. Stem cells have the ability to divide indefinitely, meaning they can produce new cells.  These cells produced of stem cells can develop into many different cell types. MSCs, which come from adult tissues, can develop into a number of cell types, including bone, cartilage, fat, and other connective tissue types. This varied developmental potential means MSCs may be useful for a variety of different treatments

One outstanding question regarding MSCs utility as therapeutic tools is that we still do not know how long MSCs remain at a injury site once implanted. We need to be certain that MSCs will persist long enough to regenerate damaged tissues. This specific question is the aim of our current research.

First, we want to provide data that shows horse MSCs inhibit inflammation within the animal. We know MSCs can do this in a petri dish, but it is important to make the connection from petri dish-results to real-life effects. My research design is to identify biomarkers, or biological indicators, of different disease states and then track these markers in response to MSC therapy. We are currently investigating different diseases in horses that involve bone, ligament and cartilage, which all parallel injuries that human athletes frequently suffer from. We are examining blood biomarkers sampled from a vein at the injury site (the foot), and also from a general circulating vein in the horse’s neck. Biomarkers sampled closer to the injury site will help us understand how the body is responding locally to the disease or injury. Biomarkers examined further away (in this case, the neck) may not be detectable or accurately reflect what is happening right at the site of injury.

We hope our research will help the field better understand the biological process associated with injury or disease, as well as provide information about the role of MSCs as a therapeutic intervention. This study will provide the first evidence that stem cell therapy in horses can alter the disease state and inhibit inflammation. It may even give insights into the molecular basis of MSC regeneration. While this study will directly improve the use of stem cell therapy in animals, it could also help improve or expand the use of stem cells in human medicine.

When we combine veterinary and human medicine and work together as a team, we can speed up the pace of research aimed at generating stem cell therapies. This benefits our furry friends, as well as the rest of us. Just imagine, in the next 10 years, you may be able to get stem cells to treat that knee injury that never healed. With veterinary and human scientists working together the possibilities are endless!

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Growing Liver Organs to Save Lives

Dane Coleal-BergumBy Dane Coleal-Bergum

When a car’s brake light goes out, or a bicycle needs a new tire because the old one goes flat, what do you normally do to fix the problem? The answer is pretty straightforward: You get a new part to replace the old defunct one.

But what happens when the component that goes bad is part of a living, breathing system? What if it’s an organ?

Organ failure is caused by extensive tissue damage that prevents an organ from performing its vital function to the body. Organ failure usually results in death without medical intervention. Unfortunately, unlike the aforementioned examples of bike tires and brake lights, medical technology hasn’t reached the point where we can simply get replacement organs off a shelf at the local parts store to replace old broken ones. Right?

Technically, the answer is yes - we are a long way away from having ready-to-go organs available for patients who desperately need them. But we may be getting close to being able to make new organs for individuals who require transplants but are stuck on waiting lists.

Chronic liver disease is an example of a condition that commonly leads to organ failure and affects around 36,000 Americans. Chronic liver disease, including cirrhosis, develops over time for a number of reasons. Exposure to hepatitis B or C, alcohol abuse, and metabolic disorders like obesity and diabetes can all cause chronic liver damage. However, regardless of the root cause, the consequence is the same: a buildup of scar tissue within the liver, which eventually results in liver failure and, ultimately, death.

Currently, there is only one way to treat chronic liver disease once it has progressed to the point of organ failure –transplantation. Alas, there are extensive waitlists for organ transplants because donor organs are in short supply. As a result, 16,000+ individuals who desperately need new livers will wait anywhere from 3 months to 5 or more years, if they manage to survive that long.

This is where new research under the guidance of Dr. Ping Zhou at the University of California, Davis comes into play.

We have been investigating embryonic stem (ES) cells as a potential therapeutic answer to chronic liver disease. ES cells are pluripotent meaning they are capable of becoming any type of cell within the body, including liver cells. ES cells are also very easy to work with and can be grown in a petri dish indefinitely. Dane Figure 1

Using ES cells, we have created endothelial cells (cells that make up the walls of blood vessels) and hepatoblasts (cells that are capable of becoming adult liver cells, as well as bile duct cells). Figure 1 shows images we created of these cells.

By growing these different liver cell types together in a petri dish, we were able to create tiny organs, or “organoids”, that resemble the basic structure of the liver.

Figure 2 shows the organization of the cells within the organoids.  The green color outlines the blood vessels that have self-organized within the tissue, while the red color shows cells that will become adult liver cells. The blue stain is indicative of cell nuclei. Dane 2

It is exciting that these organoids look like a liver, but it’s also important to know if they function like a liver as well. We’ve been investigating the function of the organoids in a petri dish and in an animal model to determine whether they perform their intended biological function and have some very promising results!

This research is proof of concept that it might be possible to grow human organs and eliminate the need for donors. This is incredibly exciting as it could mean saving the lives of thousands of people suffering from chronic liver disease, and preventing future suffering.

There are a number of questions science must address before we reach that point, including:

How do liver organoids perform over long periods of time?

How would one go about creating large-scale versions of these organoids for transplantation into larger mammals?

Is there any risk of cancer associated with using embryonic stem cells to generate these organoids?

Based on my experience in Dr. Zhou’s lab, I am confident that it is only a matter of time before we are successful in finding these answers and making this life-saving treatment a reality. 

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A Step Closer to Curing Multiple Sclerosis

Christopher CroteauBy Christopher Croteau

A family member shrieks from across the room and that’s when a loved one realizes their arm has been resting on a hot surface…and according to the burn it must have been there awhile. Normally there would be a quick reaction to move the arm away; however, this individual had no idea their arm was even touching a hot surface, much less resting on it. This is one of the first symptoms of Multiple Sclerosis (M.S.), a debilitating neurodegenerative disorder.

This horrific disease can progress rapidly; one day a person might be playing their favorite sport when all of a sudden they are unable to even walk without assistance. Many of the 2.5 million people affected worldwide by M.S. are burdened by a variety of health complications later in life (1). Lack of bladder control and buildup of food in the lungs (due to difficulties chewing and swallowing) can increase risk of bacterial infection and ultimately decrease life expectancies by an average of six years (2).

Loss of sensory and motor control is caused by the destruction of a fatty sheath called myelin that covers neurons. Neuronal extensions termed axons are much like cables used to send a message. Myelin functions as the plastic coating to these cables.  If you remove the plastic coating from cables, the signal goes haywire. Similarly, damage to myelin leads to inefficient communication between neurons. Chris Fig 1

To date (March 2016), there is still no approved treatment to promote the myelination of axons. Understanding myelin synthesis in the central nervous system will be crucial for generating therapies that can successfully remyelinate damaged regions of the brain and spinal cord.

So what do we currently know about myelination? A cell type called oligodendrocytes generates myelin (3). Mature myelinating oligodendrocytes can be formed in the adult brain from a source of cells termed oligodendrocyte progenitor cells (OPCs) (3). Unfortunately, the capacity for myelin repair is limited in M.S because few OPCs fully develop into mature myelinating oligodendrocytes at the damaged sites (3).

In the lab of Dr. David Pleasure at UC Davis at the Institute For Pediatric Regenerative Medicine at Shriners Hospital For Children Northern California, we are invesitgating a gene - that I will refer to here as FX, for Factor X (until this work is published) - that promotes neural development and represses non-neuronal cell fates in embryonic stem cells. Even though FX has been studied for its involvement in neural development, less is known about how FX impacts oligodendrocyte development in the central nervous system.

Mice have many similarities to humans in how the brain and spinal cord develops making them an ideal model organism for our research.

Chris Fig 2To understand the function of FX in OPCs, the FX gene was specifically deleted in OPCs in newly born mice. Deleting FX in OPCs resulted in a drastic decline in the number of OPCs and mature oligodendrocytes. The number of self-renewing oligodendrocytes was also reduced.

In the surviving oligodendrocyte population, we found that loss of FX decreased expression of other genes responsible for myelin production.

Our findings suggest that FX is necessary for oligodendrocyte development, and is also vital for the extent of central nervous system myelination. The next step will be measuring what happens when oligodendrocytes produce excess FX. If overexpression of FX leads to increased oligodendrocyte development and myelin synthesis it could mean an effective treatment or even cure for MS might be around the corner.

References

  1. Browne, P., Chandraratna, D., Angood, C., Tremlett, H., Baker, C., Taylor, B. V., & Thompson, A. J. (2014). Atlas of Multiple Sclerosis 2013: A growing global problem with widespread inequity. Neurology83(11), 1022–1024.
  2. Scalfari, A., Knappertz, V., Cutter, G., Goodin, D. S., Ashton, R., & Ebers, G. C. (2013). Mortality in patients with multiple sclerosis. Neurology81(2), 184–192.
  3. Huang, Hao, Zhao, Xiao-Feng, Zheng, Kang, & Qiu, Mengsheng. (2013). Regulation of the timing of oligodendrocyte differentiation: mechanisms and perspectives. Neuroscience Bulletin, 29(2), 155-164.

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Stem Cell Attachment and the Unpredictable Nature of Science

Hannah FoxBy Hannah Fox

You’ve probably heard about the promise of stem cell research. Stem cells naturally transform from an undifferentiated “stem” state into all the cell types that make up the body: heart, brain, bone, skin… you name it! Ongoing research may soon result in stem cell therapies for a diverse group of incurable diseases.

Consider a disease like diabetes. Type II diabetes is a growing epidemic in the U.S. and often causes severe complications including chronic sores on the feet of diabetic patients. In diabetic limbs small cuts can degenerate into inflamed, bacteria ridden, non-healing ulcers. What happens when infection kills all the surrounding tissue in a sore? Gangrene. What follows gangrene? Amputation.

Recent studies suggest that specific stem cells, called mesenchymal stem cells, can promote wound healing in diabetic sores. These stem cells have the potential to transform into new skin cells and secrete therapeutic molecules when placed in a diabetic wound. Bringing stem cells to the clinic may permanently save the limbs of nearly 30 million diabetics in the U.S. alone (www.cdc.gov/features/diabetesfactsheet).

In order to make stem cell mediated therapy a reality we must figure out how to effectively deliver cells to a wound site. Currently, stem cells often fail to attach and stay in the surrounding tissue when grafted into a wound. This triggers cell death a few days after treatment and thereby cuts short the therapeutic capacity of stem cells. Improvement of stem cell attachment may increase stem cell survival and therefore promote wound healing in chronic sores. One goal of the Maverakis laboratory is to advance current treatment models by targeting stem cell attachment.

Let me start with an analogy to demonstrate the mechanism of cell attachment. If you were a stem cell trying to stay attached to a wound you would need two things: (1) something to hold onto and (2) something to hold on with (your hands, for example). 

Cells have their own type of hands called integrins. Integrins protrude from cells and grab onto the surrounding environment. The Maverakis lab studies Fox blog these integrin hands, and engineers small molecules in the lab that integrins can bind/hold onto in an effort to increase cell attachment. Recently, we found that stem cell integrins efficiently grab ahold of one our engineered small molecules, a peptide composed of a specific combination of amino acids. If we put this specific peptide into diabetic wounds along with stem cells, perhaps the stem cells could better engraft into a wound site (as depicted in figure 1).

So we have the cell hands (integrins) and a candidate for the hands to grab onto (peptide) to anchor the cells. The next important step was investigating the interaction between cellular integrins and our peptide to determine if binding only facilitated anchoring, or if it also caused an altered cell response.

Cells often times react to what they sense in the environment with their integrin hands. And their responses vary greatly: cells can proliferate, differentiate into other cell types, and even commit cell suicide by a process called apoptosis if there is nothing around to take hold of. Responses are largely based on the specific molecule the cell is holding onto.

Our recent experiments suggest that the integrin—peptide interaction causes stem cells to differentiate into bone cells. Growing new bone on the skin surface was not exactly the effect we expected when we started studying this molecule. This altered differentiation profile may ultimately prevent this particular peptide from being used in a superficial skin setting.

But the possibility of this peptide being used in therapy may not be lost. After all, growing bone is a good thing under the appropriate non-skin circumstances. A variety of brittle bone diseases have a detrimental impact on the lives of affected persons. Osteoporosis and low bone mass affect the elderly, leading to broken bones after small missteps or big coughs. This disease incapacitates over 50 million people in our senior population, according to the National Osteoporosis Foundation. Some brittle bone diseases also affect children. The inherited disease osteogenesis imperfecta causes bones to break for no apparent reason and often results in infant death.

This peptide has high potential for use in stem cell treatments related to bone disease. That being said, the Maverakis lab continues to work hard to improve stem cell mediated treatment of chronic wounds. We are discovering and analyzing a variety of similar small peptides, some of which are showing great promise for facilitating wound healing. Stem cell treatment remains likely for the future of those affected by diabetic sores.

Science necessitates adaptability. When experimental results differ from previous predictions there are two choices: give up or proceed in a new direction. We have chosen the latter. The Maverakis lab seeks to understand a wide variety of diseases, from the skin and inward, and works with diligence to discover mechanisms by which these diseases can be ameliorated with stem cells.

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A Promising Future: An Alternative to Electronic Pacemakers

Hillary KaoBy Hillary Kao

The human heart is a powerful, muscular pump.  It contracts continuously to circulate oxygenated blood throughout the entire body. 

The heart is comprised of 3-5 billion specialized cells called cardiomyocytes. Unlike most organs of the body, the heart is unable to regenerate itself if any of its cells are damaged, which often occurs as a result of cardiovascular diseases.

Cardiovascular disease can also cause arrhythmia, a term used to describe an abnormal heartbeat.  Left untreated, arrhythmias can cause fainting, shortness of breath, damage to other organs, stroke, or sudden cardiac arrest.  There are several different types of arrhythmia.  One in particular is called sinus node dysfunction, where the heart’s natural pacemaker generates an abnormally slow heart rhythm.  This type of arrhythmia has a prevalence between 403 and 666 per million.  Depending on the severity, doctors may treat such a condition by implanting an electronic pacemaker. 

An electronic pacemaker is a small battery operated device that generates electrical impulses, which are delivered through implant leads, to stimulate the heart to beat at a normal rhythm. Hillary 1

Although current pacemakers work quite well, they also have their limitations.

For instance, pacemaker implantation is expensive.  The device itself is about $58,000, but also involves costly surgery and hospital stay.

Adding to the cost and inconvenience, pacemakers require ongoing maintenance. Invasive surgery is needed for battery replacement (every 5-12 years), in the event of lead failure, or for changing short leads in growing pediatric patients.  Not to mention, pacemakers are susceptible to magnetic interference, which can disturb or deactivate its function.

Scientists working in the field of regenerative medicine are hopeful that their work will relegate pacemakers to ancient medical history. Regenerative medicine involves the use of stem cells to “regenerate” lost or damaged tissues. The most multi-faceted type of stem cell is the pluripotent stem cell (PSC). “Pluripotent” refers to the ability of these stem cells to develop into any cell type within the body.

This defining property of PSCs qualifies them as candidates for a wide variety of research and potential therapies.  However, their use has been controversial; human embryonic stem cells (hESCs) were the first identified source of PSCs.  Many people object to the use of hESCs because the derivation process involves early stage human embryos.

In recent years, scientists have found a way to avoid using of hESCs by creating what is known as human induced pluripotent stem cells (hiPSCs).  Scientists can generate hiPSCs by reprogramming normal skin cells. A few genes (that are usually found in the human egg cell) are added to the skin cells, which changes the skin cells into embryonic-like cells that are pluripotent and, therefore, have regenerative properties.

There are significant advantages to using hiPSCs in experimentation: 

  • They are relatively easy to generate.
  • They behave similarly to hESCs in their ability to remodel themselves into any specialized cell-type.
  • There are no ethical issues surrounding their use because human embryos are not used in the derivation process.
  • Because hiPSCs can be made from a patient’s own skin cells, there are no issues with immune rejection.

Because of these advantages, many scientists within the field of regenerative medicine now prefer using hiPSCs.

One of these scientists is Dr. Deborah Lieu at the University of California, Davis – Institute for Regenerative Cures. She is using hiPSCs to make “pacemaking” heart cells to try to treat arrythmia. These specialized heart cells have the ability to control the beating of the heart. Dr. Lieu’s ultimate goal is to use hiPSC-derived pacemaking cells to create a “bio-pacemaker” that could serve as an alternative to current electronic pacemakers.

Kao 2The first step is figuring out how to create pacemaker cells from hiPSC cells. To do this, Dr. Lieu’s research team must figure out how to mimic conditions within the human embryo that guide pacemaker heart cell development. They are doing this by adding specific cocktails of small molecules and cell culture media at exact time points to very precisely guide cell development.

Once the hiPSC-derived pacemaking heart cells reach maturity, Dr. Lieu and colleagues plan to examine them using different experimental analyses.

Thus far, most research in this area has focused largely on another type of heart cell called contractile heart cells, meaning there is still a lot to be learned about pacemaker cells before they can move from the laboratory to patient bedside.

Dr. Lieu’s group will use microscopic analysis to examine cell shape and protein configuration inside the hiPSC-derived pacemaking heart cells and make comparisons to both normal pacemaker cells and contractile cells. They can also measure differences in what types of genes are expressed in these cells by quantifying the content of different proteins (which are coded for by genes).

It will be particularly critical to examine the electrical membrane potential, also called the action potential (AP), of the hiPSC-derived pacemaking heart cells. Pacemaker heart cells have a distinct AP that is different from other regions of the heart. If these hiPSC-derived cells are to be used therapeutically, it is essential that they retain the normal APs found in native pacemaker heart cells.

At present, Dr. Lieu and colleagues continue their research.

Once they have successfully generated hiPSC-derived pacemaking heart cells, they hope their research will be utilized for other applications, such as, drug toxicity testing, patient-specific hiPSCs for studying cardiac dysfunctions, and personalized medicine. 

References

Bergmann, O., Bhardwaj, R. D., Bernard, S., Zdunek, S., Barnabe-Heider, F., Walsh, S., . . . Frisen, J. (2009). Evidence for cardiomyocyte renewal in humans. Science, 324(5923), 98-102. doi:10.1126/science.1164680

Hyslop, L. A., Armstrong, L., Stojkovic, M., & Lako, M. (2005). Human embryonic stem cells: biology and clinical implications. Expert Rev Mol Med, 7(19), 1-21. doi:10.1017/S1462399405009804

Lieu, D. K., Fu, J. D., Chiamvimonvat, N., Tung, K. C., McNerney, G. P., Huser, T., . . . Li, R. A. (2013). Mechanism-based facilitated maturation of human pluripotent stem cell-derived cardiomyocytes. Circ Arrhythm Electrophysiol, 6(1), 191-201. doi:10.1161/CIRCEP.111.973420

Mozaffarian, D., Benjamin, E. J., Go, A. S., Arnett, D. K., Blaha, M. J., Cushman, M., . . . Turner, M. B. (2016). Heart disease and stroke statistics - 2016 update: a report from the American Heart Association. Circulation, 133, e38-e360. doi:10.1161/CIR.0000000000000350

Schram, G., Pourrier, M., Melnyk, P., & Nattel, S. (2002). Differential Distribution of Cardiac Ion Channel Expression as a Basis for Regional Specialization in Electrical Function. Circulation Research, 90(9), 939-950. doi:10.1161/01.res.0000018627.89528.6f

Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131(5), 861-872. doi:10.1016/j.cell.2007.11.019

Yamanaka, S. (2007). Strategies and new developments in the generation of patient-specific pluripotent stem cells. Cell Stem Cell, 1(1), 39-49. doi:10.1016/j.stem.2007.05.012

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Breath of Fresh Air: Regenerative Medicine Bringing Hope to Patients Needing New Airways

By Josh Martinez

For the many thousands of patients suffering from diseases of the airway, life can be a constant struggle to get enough air. Injury, disease, tumors and developmental abnormalities of the windpipe leave many patients persistently suffocating.

One such person, Claudia Castillo, was suffering from a collapsed airway damaged by a severe case of tuberculosis (shown in the CT image on the right).

The 30-year-old mother of two children was living in a state of constant suffocation. Her shortness of breath was so severe that she could barely get enough air in her body to keep up with her two children or climb a flight of stairs. Claudia desired nothing more than to return to her normal life. The problem was that the only medical procedures available were very risky and would’ve likely left Claudia with a poor quality of life.

Just when it seemed Claudia was out of options, a team of surgeons and biomedical researchers offered her a revolutionary alternative: an experimental transplant with a trachea that would be made using her own stem cells. Scientists had used this procedure successfully with rats and pigs, but it had never been attempted in a human.

Claudia took a risk and agreed to make medical history by becoming the first human patient to receive this this new transplant technology. Windpipe tranplant scheme

Figure 1 shows the steps that Dr. Martin Birchall and a team of pioneering throat surgeons took to construct Claudia's airway replacement.

1.  A donor’s trachea was removed

2. The donor trachea was treated with chemicals to strip away all of the cells leaving behind only a protein scaffold.

3. This scaffold was seeded with adult stem cells from Claudia’s bone marrow to replace the tracheal cartilage. The inside of the scaffold was seeded with airway cells scraped from Claudia’s healthy bronchus. Claudia’s cells repopulated the scaffold to form her airway replacement.

4. The new airway construct was then transplanted into Claudia to replace the damaged portion of her airway. As a bonus, Claudia did not require the use of harsh immunosuppressive drugs because the immune system does not reject cells or tissues it recognizes as “self.” Dr. Birchall

Years later, Claudia has had no post-surgical complications and gives credit to this procedure for giving her back a normal life. In his recent STEM lecture at Sac State, Dr. Birchall (shown in figure 2) described Claudia’s miraculous procedure, as well as his work replacing a child’s trachea using a similar procedure. These medical breakthroughs have established the feasibility of fabricating tissues and organs using patients’ own cells, and have revolutionized transplantation using tissue engineering.

There is an ever-increasing population of patients in need of transplants and an extremely short supply of donor organs, demonstrating the clinical need for an innovative new solution. Tissue engineering and regenerative medicine is a breath of fresh air for biomedical research, and is poised to revolutionize the way we look at medicine. Tissue engineering involves growing 3D tissues and organs in a lab and then using them to replace, repair or reconstruct body parts. This technology can overcome two major limitations with transplantation: the shortage of donor tissue available to patients in need and the complications associated with the use of harsh drugs required to prevent rejection of transplanted tissue.

To bioengineer an airway replacement, scientists must regenerate a layer of cells called “airway epithelium” that will line the inside of the windpipe. Unfortunately, there is little known about how to effectively regenerate the airway epithelium, so this has been a great challenge. One part of the challenge is figuring out the best source of cells (that would be taken from the patient) to use to make the new airway epithelium. 

Airway EpitheliumThe airway epithelium (figure 3) is a specialized protective barrier that uses mucous to trap germs, particles, and cells with finger-like structures called cilia, which escalate the mucous away from the lungs. Making sure the new airway epithelium provides this protective function is key to the survival of the bioengineered trachea. Without knowing how to effectively regenerate airway epithelium, we cannot utilize tissue engineering on a large scale for replacing large segments of airways.

Obtaining epithelial cells from the airway requires a biopsy, which can be dangerous for a patient population that already has airway complications. Damaged airways also means patients will have limited healthy airway tissue available to biopsy. Furthermore, when scientists try to grow cells in a petri dish from airway biopsies they have found the biopsied cells do not create enough epithelial cells to completely regenerate a trachea. It is therefore critical for other sources of epithelium to be investigated for their potential to regenerate airway epithelium.

In the laboratory of Dr. Alice Tarantal, at the University of California, Davis we are focused on finding a more feasible epithelial cell source to line the inside of a bioengineered airway construct, and we have a promising candidate (stay tuned for an update as to what this tissue is; yes, I am leaving you with a cliffhanger).

Tissue engineering can improve and even save lives of many, like Claudia, in need of a new organ. Surgeons and scientists at UC Davis are currently working to establish safe and effective methods for constructing and implanting airway replacements using animal models to enable movement of this technology to human clinical trials. While we have already demonstrated the possibility of utilizing this technology, preclinical studies like those being done at UC Davis are moving us closer to making stem cell cures a reality for all patients.

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Paramedic Activity of MSCs Utilized in Tunable Hydrogel for Chronic Wound Treatment

Nora RimpoBy Nora Rimpo 

Type II diabetes is a chronic disease that is sweeping our nation like a pandemic.  The incidence of diabetes has soared from a meager 1% in 1960 up to 7% today, currently affecting 29 million individuals in the U.S.1 An estimated $245 billion dollars are spent annually on diabetes related care.

Patients with diabetes are at an increased risk for developing wounds that do not heal. Current treatment options include gauze dressings or skin substitutes, which are biological or synthetic products that mimic properties of skin, to aid in wound healing. Patients that do not respond to treatment require amputation to prevent death from life-threatening infections. Approximately 71,000 diabetic patients will require amputation each year.3 Therapeutic advancements are urgently needed to provide patients with a better quality of life and to decrease the costly burden afflicted on our healthcare system.

Wound healing occurs like an orchestrated symphony, but the process can quickly go awry in a diabetic patient requiring therapeutic intervention.5 The research lab of Dr. Maverakis at the Institute for Regenerative Cures, UC Davis, is developing a treatment option using mesenchymal stem cells (MSCs). This cellular therapy is based on cutting edge research and resembles a fancy cell-based band-aid. Chronic wound

So, what are MSCs and what do they have to do with wound healing? MSCs are a type of stem cell referred to as “multipotent.” Multipotent means the MSCs have “multiple potentials” when they begin to develop into adult cell types. In the case of MSCs, their multipotency refers to their ability to   develop into different connective tissue cells types (e.g., bone, muscle, fat, dermal cells), but nothing else. Studies have shown that MSCs also affect immune system activity; for example, they can promote healing through accelerated closure of wounds and also improve blood vessel formation.6 In fact, MSCs are sometimes referred to as the “paramedics of the body” because of their ability to help repair damaged tissues. 

To create a cell-based band-aid that can be placed over a wound to promote healing, a substance called a hydrogel is used. The hydrogel acts as a delivery platform for MSCs to the wound while also maintaining an optimal environment for MSC survival. The therapeutic benefits of MSCs would be useless if the cells could not be localized or survive long enough for their benefits to be realized. This is where our research comes into play.

HydrogelYou feel most relaxed when you are at home, right? MSCs act in similar ways. Their home is the human body and the cells can sense when their local environment changes. The hydrogel we plan to construct will create a mock home for the cells that mimic the body’s environment and allows for the cells to survive and thrive at the site of the wound.

In addition, the cells must be kept at the site of the wound and not allowed to wander off. Just as a person uses a leash to keep a pet nearby, we have developed a mechanism that maintains the MSCs at the wound area. This system works by using protein receptors called integrins that are found on the surface of MSCs. Integrins interact with the environment and signal to the cell. We found a new small molecule (a peptide) that MSC integrins specifically recognize. This peptide will tether the cells (via their integrins) to their surrounding environment and keep them from straying.

We have studied what this peptide-integrin interaction does to the cell and it appears to increase expression of genes that participate in wound healing. This finding is key for improvement of chronic wound therapies. Embedding the peptide in the hydrogel will both retain the MSCs at the wound area and promote healing.

The next step in our research will use a mouse model of wound healing to further study the peptide-integrin interaction.  With this model we will be able to learn even more about the biological effects of the hydrogel and provide more evidence to support initiation of clinical trials. Looking ahead, this MSC based therapy has the potential to solve a serious problem currently facing our healthcare system and improve the quality of life of millions of suffering patients. 

References

  1. Geiss LS, Wang J, Cheng YJ. Thompson TJ, Barker L; Li Y, Albright AL, Gregg EW. Prevalence and incidence trends for diagnosed diabetes among adults aged 20 to 79 years, United States, 1980-2012. JAMA 2014; 312:1218-1226.
  2. Center for Disease Control and Prevention. National diabetes fact sheet: general information and national estimates on diabetes in the United States, 2007. U.S. Department of Health and Human Services, CfDCaPCenters for Disease Control and Prevention; Atlanta, GA: 2008.
  3. Halim, A. S., Khoo, T. L., & Shah, J. M. Y. (2010). Biologic and synthetic skin substitutes: An overview. Indian Journal of Plastic Surgery43(3), 23.
  4. Bauer E. Sumpio, “Contemporary Evaluation and Management of the Diabetic Foot,” Scientifica, vol. 2012, Article ID 435487, 17 pages, 2012. doi:10.6064/2012/435487
  5. Patrick S. Murphy and Gregory R. D. Evans. Advances in Wound Healing: A Review of Current Wound Healing Products, Plastic Surgery International, vol. 2012, Article ID 190436, 8 pages, 2012. doi:10.1155/2012/190436
  6. Chen, S. et al. Mesenchymal stem cell-laden anti-inflammatory hydrogel enhances diabetic wound healing. Sci. Rep.5, 18104, 2015. doi: 10.1038/srep18104

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Specific Histone Gene may be a Key Player in Brain Development

Allison WagnerBy Allison Wagner 

The devastating diagnosis of childhood gliomas accounts for 20% of childhood cancers and affects 100,000 families every year in the United States ("Survival rates for selected childhood brain and spinal cord tumors," 2014). Gliomas are tumors  found in the central nervous system that often cause swelling and pressure on the brain. Although aggressive treatment involving surgery, radiation, and chemotherapy is used, the five year survival rate of patients with treatment is only 15-35% (Miller, 2013). Our research is dedicated to finding the causes of gliomas in order to facilitate development of more effective treatments.

A remarkable new discovery in 2012 provided clues as to how these pediatric cancers may develop. When examining 48 glioma samples from patients, scientists noticed a recurring mutation in a gene called H3f3a (Schwartzentruber et al.). Genes are segments of DNA that contain instructions for making specific proteins needed by the cell. The H3f3a gene encodes a protein that is critical for the structure of chromatin. When H3f3a is mutated, it alters the chromatin structure and often leads to cancer development. So what is chromatin?

Chromosomes are inherited structures composed of DNA. Chromosomal DNA within our cells is packaged by being tightly coiled around proteins called histones (figure 1). The combination of DNA and histone proteins is referred to as chromatin. Chromatin

Chromatin is similar to a string of holiday lights - the DNA being the electrical wire and the histones being the brightly colored lights. Just as there are different colored bulbs on holiday lights, there are also different kinds of histones. There are four main types of histone proteins that come together in different combinations to form an octamer histone “core.” DNA wraps around these histone cores; an individual histone octamer plus its wrapped DNA is called a nucleosome.

The histone proteins influence the physical state of the DNA leading to activation or inactivation of genes. For example, a modification could remove the “stickiness” of a histone protein for the DNA, thereby causing the DNA to become unwound. This exposes the DNA in a way that allows other factors to bind the DNA and potentially turn on genes. The different types of histones can cause different genes to either be turned off or on.

How histones bind DNA is critical; when genes are incorrectly turned on or off it can lead to cancer (depending on the gene).

One histone variant in particular has caught the eye of scientists for its special properties and its connection with pediatric gliomas. H3.3 present in normal brain cells and mutated H3.3 is found in childhood brain cancers. We know that H3.3 is required for brain cells to function normally, but when it is mutated H3.3 can cause drastic, life-threatening changes in the cells.

The H3.3 histone protein can be created from two different genes, H3f3a or H3f3b. Mutations in the DNA sequence of the H3f3a gene are known to cause to pediatric gliomas, while less is known about the H3f3b gene. Both genes are currently being studied in the laboratory of Dr. Paul Knoepfler at the UC Davis Medical Center in partnership with Shriner’s Hospital.

We have genetically altered mice by manipulating either the H3f3a or H3f3b gene. Subsequent analysis of mutant mice has led to interesting discoveries about similarities and differences between H3f3a and H3f3b. We are currently investigating how and why these genes are different and are hopeful it will shed light on the mechanism of H3.3-based glioma formation. Discovery of the exact functions of the two genes may lead to a better understanding of normal brain development.

Our studies of histone H3.3 are bringing us closer to uncovering how gliomas develop, which is a significant step in the right direction toward finding a cure for this devastating pediatric cancer.

References

  1. Miller, T. P. (2013). All About Pediatric Gliomas (Low and High Grade). Retrieved from OncoLink website: http://www.oncolink.org/types/article.cfm?c=393&id=9660
  2. Schwartzentruber, J., Korshunov, A., Liu, X. Y., Jones, D. T., Pfaff, E., Jacob, K., . . . Jabado, N. (2012). Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature, 482(7384), 226-231. doi:10.1038/nature10833
  3. Survival rates for selected childhood brain and spinal cord tumors. (2014). Brain and Spinal Cord Tumors in Children, 2016. Retrieved from http://www.cancer.org website: http://www.cancer.org/cancer/braincnstumorsinchildren/detailedguide/brain-and-spinal-cord-tumors-in-children-survival-rates

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Looking for a Cure to Spina Bifida using Different Mesenchymal Stem Cell Sources

Scott WalkerBy Scott Walker 

If you’ve ever known a person with Spina Bifida, the words may conjure up images of them unable to walk without the use of metal leg braces or crutches. If this person had a severe form of the disease, you also know about the excess cerebrospinal fluid that can build up until it has to be drained from their head by a shunt.

Spina Bifida is a birth defect caused by impaired development of the spinal cord. When the spinal cord develops normally, a flat layer of cells forms a closed tube (just imagine rolling up a piece of paper into a tube – same thing). In people with spina bifida, the tube does not close all of the way. This so called “neural tube closure defect” causes damage to neurons within the spinal cord. Death of spinal cord neurons can lead to paralysis and a deadly condition known as hydroencephalus in which fluid accumulates on the brain and has to be drained through an implanted shunt. Severe cases can also cause a portion of the spinal cord to jut out of the newborn baby’s back.

A cutting edge new surgical treatment seeks to cure this congenital disease before it can inflict any of these horrors. This treatment would use stem cells derived from a baby’s own placenta. (Placenta develops from the same early embryonic cells that the actual embryo does, so they carry the same genetic make-up).Walker figure

A routine in utero diagnostic procedure can be used to safely harvest a small piece of placental tissue from the pregnant mom. The placenta is a rich source of specific types of adult stem cell called the Placental Mesenchymal Stem Cell (P-MSC). It turns out that P-MSCs can repair neurons in the spinal cord without directly replacing them.2

The hope is that a baby’s spinal cord could be repaired using the amazing regenerative properties of these cells while the baby is still in the womb.

P-MSCs act as little cell factories by constantly pumping out a veritable plethora of proteins signal to nearby cells to thrive and grow1. These proteins can even suppress the immune system, which can reduce potentially harmful inflammation and promote the growth and survival of surrounding cells.3 A truly unique and powerful ability; P-MSCs do not actually become part of the tissue. They act for a few weeks to a month before disappearing forever, but it is all the time they may need to provide life-changing benefits for countless unborn babies.

It turns out the placenta is not the only safe way to obtain an MSC from a developing baby. Thus, we are currently investigating other safe sources of MSCs for their potential to treat spina bifida, and are focusing on one particular alternative to determine if these MSCs are even more effective at healing damaged spinal cord neurons and, therefore, might provide a more potent treatment for spina bifida

Comparing these two different cell types was the focus of my work in the laboratory of Dr. Farmer and Dr. Wang at University of California, Davis – Department of Surgery.

Direct comparison of two cell types can be challenging because if the cells come from different donors, they would naturally have genetic differences (all people have different genetic profiles). Thankfully, in our study we were able to obtain both MSC types from a single donor, eliminating all the genetic variation that occurs between different people’s cells.

Cells isolated from different tissues may be very different from each other in several important protein messages, chief among them being a class of proteins called growth factors. Different growth factors have different functions, like promoting the formation or regeneration of vascular tissue (think blood vessels), or aiding in development and function of neural tissue (which could be particularly instrumental for neuron protection in the aforementioned surgical intervention for spina bifida).

Our work is aimed at elucidating how these protein profiles vary within the two different MSC populations, which could ultimately translate into important real world applications for MSC source selection in the treatment of spina bifida.

We are hopeful our findings will ultimately help provide successful and safe regeneration of neurons in fetuses that would otherwise be born with spina bifida.

References

  1. Wegmeyer H., Broske AM., Leddin M., Kuentzer K., Nisslbeck A., Hupfeld J., Wiechmann K., Kuhlen J., Schwerin C., Stein C., Knothe S., Funk J., Huss R., Neubauer M.  Mesenchymal stromal cell characteristics vary depending on their origin.  Stem Cells Dev.  2013; 22(19): 2606-2618.
  2. Wang A., Brown E., Lankford L., Keller B., Pivetti C., Sitkin N.,  Beattie M., Bresnahan J., Farmer D.  Placental mesenchymal stromal cells rescue ambulation in ovine myelomeningocele.  Stem Cells Trans Med.  Published online April 24, 2015.
  3. English K., Ryan J., Tobin L., Murphy M., Barry F., Mahon B.  Cell contact, prostaglandin E2 and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4+CD25Highforkhead box P3+ regulatory T cells.  Clinical and Exp.  Immunology.  2009; 156: 149-160.

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Editorials

What is an Induced Pluripotent Stem Cell?

Vanessa AguilarBy Vanessa Aguilar

How is it that we can see a beautiful morning sunrise, taste a delightful morning cup of coffee, or feel our heart pumping blood through our body during a light jog? The biological answer is: because of our cells! Cells are the smallest building blocks of life and we are made up of trillions of them (Bianconi et al., 2013). Every thought, smell, taste – in fact, our complete existence – is a result of their intricate network of communication and multifaceted functions.

There are many different types of cells in our body. Most cells are “specialized,” meaning they perform a very specific function. For example, the retina is made up of cells called rods and cones that allow us to see light and color, respectively.

Although most cells have specific roles, they all start out with the same set of instructions. Cellular instructions come in the form of genes, which are encoded within DNA and housed within the nucleus of our cells. During embryonic development cells become more and more specialized due to gene regulation: a different pattern of genes are turned on in different cell types. It is the specific set of genes that are up-regulated (turned on) or down-regulated (turned off) that ultimately determine the type of cell it will become.

For example, genes that are important for seeing light are up-regulated in a rod cell, while genes important for seeing color are up-regulated in a cone cell.

Once a cell becomes specialized, it usually loses the ability to divide. That means if your cone cells are damaged, the remaining cone cells cannot divide to replace the cells that are damaged in your retina. Your vision would be irreparably damaged.

For many tissues, this is where stem cells come into play.

Stem cells have the capacity to divide and make new cells for a long period of time. Our stem cells help replenish lost, aging, or damaged cells throughout our body. Importantly, stem cells create both more stem cells and cells that will eventually become specialized.

Stem cells in adults [and, actually, stem cells after just a few weeks of embryonic development] are referred to as “adult stem cells.” Adult stem cells are limited in the type of cell they can become. For example, one type of adult stem cell that resides in our bone marrow can replenish our bone, cartilage, and blood cells, but cannot develop into any other cell type (for example, this particular stem cell could not develop into a rod or a cone cell). Therefore, adult stem cells are called multipotent due to their ability to turn into multiple cell types. This is in contrast to embryonic stem cells, which only exist in the 7 – 10 day old human embryo; embryonic stem cells are called pluripotent because of their ability to turn into ALL cell types.

Recently, scientists have figured out a way to turn a specialized adult cell (like a skin cell, seen in figure 1),skin fibroblasts into a cell with pluripotent capabilities (Takahashi and Yamanaka, 2006). This is remarkable because specialized cells usually do not divide at all, and they certainly are not pluripotent; it is a sort of molecular magic trick. These incredible cells are called induced pluripotent stem cells (iPSCs). Since these cells are pluripotent, they have the ability to become any type of cell in the body. These extraordinary cells could be a source of cells used for regenerative medicine, a branch of medicine that aims to repair damaged tissues in humans.

What I didn’t mention before is that some adult tissues do not have an adult stem cell population dedicated to replenishing cells. The retina and kidney are two examples of so-called “non-regenerative tissues.” Imagine the benefits of being able to use iPSCs to grow non-regenerative tissues like the retina…or maybe even a whole kidney! This would greatly reduce our dependence on organ donations and transplantation, a process with incredible limitations and complications.

A profound aspect of using iPSCs in medicine is that the source of adult cells used to create iPSCs can be directly from the individual receiving the stem cell treatment. This would greatly decrease the chance of immune system rejection post-treatment, which is a common complication in organ transplantation (“What is an Induced Pluripotent Stem Cell?” 2015). Also, the most common source of adult cells used to create iPSCs are skin cells, which are easily obtained and not controversial in comparison to human embryonic stem cells.

Many diseases such as cancer, diabetes, and heart disease cause tissue damage that the body is not able to repair. For example, when a heart attack occurs, there is often damage to the heart muscle that becomes scarred. This scarring causes the heart to work less efficiently and could lead to other types of heart conditions. Using iPSCs to regenerate the damaged area could alleviate the consequences of scarring and improve the quality of life for an affected individual. Regenerating the damaged area could also minimize the amount of medication (and, therefore, side effects) a person might otherwise be required to take for life.

Scientists are incredibly excited about the seemingly limitless potential of iPSCs in regenerative medicine. There is now tremendous effort in the field to figure out how to safely and effectively use these amazing cells for all different types of disease. It is a fantastic time to be a scientist working in the field of regenerative medicine.

References

Bianconi, E., Piovesan, A., Facchin, F., Beraudi, A., Casadei, R., Frabetti, F., & Canaider, S.  (2013). An estimation of the number of cells in the human body. Annals Of Human Biology, 40(6), 463-471. doi:10.3109/03014460.2013.807878

Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell126(4), 663-676.

What are induced pluripotent stem cells?. In Stem Cell Information [World Wide Web site]. Bethesda, MD: National Institutes of Health, U.S. Department of Health and Human Services, 2015 Retrieved from <http://stemcells.nih.gov/info/basics/pages/basics10.aspx>

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The Bioethics of Embryonic Stem Cell Research

Clement ArohBy Clement Aroh

Bioethics is the shared examination and application of ethical guidelines in biological research and medicine. The bioethics of stem cell research has been a center of debate, particularly regarding the use of human embryonic stem cells for regenerative cures. As a scientist working in the field of stem cell research, I view this research as a pursuit for reliable treatment alternatives for diseases that cause unspeakable human suffering. I respect that people have alternative views from mine. Here, I do not aim to change minds, but I would like to provide a framework to help you understand the history and biology of embryonic stem cells, so that you may have an informed opinion - whatever that opinion might be.

When the first “test tube baby” (in vitro fertilization, IVF), Louise Joy Brown, was born on July 25, 1978, the whole world stood in awe and received her with excitement. Many global organizations described her as a “miracle baby" (this is perhaps a bit ironic given that she is a result of applied scientific research to medicine). Later, in 1998, major public outcry regarding bioethics of stem cell research arose when the first couple donated human embryos for stem cell research for infertility solutions.  The couple had used IVF as a solution for their own infertility issues, and as is customary in the IVF process, extra early stage embryos – called blastocysts - were produced.  Since then, bioethical issues surrounding the use of embryonic stem cells has persisted.  The central concern hinges on the question: “when does life begin?” Some believe that life starts at the moment of conception, when an egg cell is fertilized by a sperm cell.  Some argue that life does not begin until the fetus has a heartbeat (5 ½-6 ½ weeks) or when the fetus can survive without the mother and so may be technically regarded as separate from her body (~20-23 weeks). Others believe that life begins at birth. While people may disagree widely on this topic, scientists certainly agree that after conception, a one-cell stage zygote is created, which has the ability to enter a developmental program with the potential to create a human being.

A common misconception is where embryonic stem cells come from. To understand this, you must first learn a bit about early development and IVF.

In the first 7-10 days following conception the zygote develops from a single cell into a sphere of about 120 cells and looks a bit like a raspberry, but is only about the size of a grain of sand. This stage of development happens in the fallopian tubes.  Once the ball of cells, referred to as the blastocyst at this stage, gets to the uterus it will hopefully attach to the uterine walls and implant.  Further development then proceeds within the lining of the mother’s uterus.

A blastocyst is what is created when a couple visits an IVF clinic.  Scientists combine sperm and egg in a petri dish and allow development to proceed to the blastocyst stage.  The healthiest looking blastocysts are then implanted into mom because otherwise development cannot proceed normally after this stage. 

Because IVF is an imperfect and arduous process, many blastocysts are usually created (anywhere from 8-30).  Often, some of the blastocysts may not appear normal, or the implantation process may not work the first, second, or even third time. Creating extra blastocysts allows scientists to select the healthiest blastocyst(s) and have multiple implantation trials.  ES Cell

The couple must then decide what to do with the remaining blastocysts.  At this stage, the cells are at such a primitive state that they can be frozen at -80 degrees for up to 10 years (which is not possible with later stage embryos). When a couple decides they will not be using their extra blastocysts, they have three choices: 1. Have them discarded as medical waste, 2. Allow them to go up for “embryo adoption” by a couple that cannot create viable blastocysts, or 3. Donate them for research.

This is where embryonic stem cells are derived from: donated blastocysts from IVF clinics that would otherwise have been discarded (assuming the couple was opposed to adoption, for their own personal reasons). It is important to stress that these cells cannot be turned into an embryo in a lab. Blastocysts need to be in a mother’s uterus to develop into a human. In the lab, these cells are removed from the spherical blastocyst, put into a petri dish, and molecular factors are added so that the cells will remain in a primitive state. By primitive I mean that all of the cells are identical little microscopic specks – there is no structure, no nervous system, no muscle cells, no heart cells, no specific cells of any kind yet. In many ways, the early blastocyst cells are like the sperm and egg themselves – they can be frozen for long periods of time, and they are all identical, individual cells, with no advanced function – but, also like the egg and sperm, these cells have potential.

Once the cells of the blastocyst are put into a petri dish, scientists can study the cells and manipulate them in ways that will allow them to develop cures for children and adults suffering from diseases ranging from congenital birth defects, cancer, diabetes, heart defects, blindness, etc.

Although I mentioned at the start of this article that I do not aim to tell you what your opinions should be, I do suggest that if you support IVF, you should understand the fact that many blastocysts end up being discarded.  And if the choice comes down to being discarded or used for research, my personal belief is that it honors that potential life much more if the cells are used to potentially create improved treatments to diminish human suffering and disease – to potentially save countless lives - rather than being discarded. 

As the Italian astronomer, Galileo said, “all truths are easy to understand once they are discovered; the point is to discover them.” When it comes to ethics, we all have our own personal truths. I am thankful that bioethicists work hard to tackle complicated questions that do not have easy answers.  Perhaps the most we can hope for is that we as a community educate ourselves so that we may understand the different considerations of bioethical debates.  We may not agree, but hopefully all sides are focused on helping people.

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Differentiating Embryonic and Induced Pluripotent Stem Cells

Nathan HaighBy Nathan Haigh

Since the isolation of human embryonic stem cells (hESC) in 1998, stem cell research has gone from being highly controversial to being a source of optimism and promise. What changed? And why does it matter?

The first hESCs came from embryos donated by in vitro fertilization clinic patients. IVF involves the combination of egg and sperm outside the body and subsequent maturation until the embryo would implant into the uterus. These embryos are incapable of developing further without implantation.

Once hESCs were discovered, beliefs that they came from aborted fetuses and imagined science fiction-style organ farms created dystopian fears. Following the 2001 ban on new Federal funding for stem cell research, a study by Virginia Commonwealth University indicated strong public support for the ban1.

When Federal funding was cut-off, states like California approved their own funding for stem cell research. This created the California Institute of Regenerative Medicine (CIRM) including the CIRM Bridges program at Sac State, where Dr. Emanual Maverakis studies treatments for chronic wounds. Haigh 1

Chronic wounds to the skin present an abnormally large burden on the healthcare system at an estimated $25 billion per year2. This includes the cost of treating infections caused by antibiotic-resistant bacteria like Methicillin-resistant Staphylococcus aureus (MRSA). Recent research suggests that mesenchymal stem cells (MSCs) may be able to reverse MRSA infection3.

The Maverakis Lab at the University of California, Davis is working on applying MSCs to chronic wounds to improve healing and, therefore, quality of life.

MSCs were first found in bone marrow and were one of the first adult stem cells discovered. But the ability to convert adipose tissue or skin cells into MSCs is far more promising than invasively harvesting adult stem cells.

The idea for inducing adult cells to become stem cells was inspired by pioneering work on animal cloning. Breakthrough experiments showed that scientists could transfer the genome of an adult cell into an egg that had the nucleus removed, and a clone of the cell donor would be born. This indicated factors in the egg somehow reverted the DNA to an embryonic state normally only found in hESCs. And in 2006, Drs. Kazutoshi Takahashi and Shinya Yamanaka  identified these factors, put them into a mouse skin cell and created the first induced plutipotent stem cells (iPSC)4.

The so-called Yamanaka factors (Oct3/4, Sox2, Klf4, and c-Myc) are master regulatory genes that cause adult cells to become iPSCs. The functional difference between iPSCs and hESCs is that iPSCs cannot become placenta and cannot implant into a uterus; therefore, iPSCs are incapable of producing a viable life. This fact circumvented some of the controversy surrounding the use of donated embryos.

The ability to produce iPSCs means a patient’s own cells could be used to produce their own stem cell-based treatment, a process called autologous transplantation. This would likely reduce or eliminate the need for immunosuppresant drugs to prevent rejection of the transplanted tissue because the patient’s body would recognize the transplanted tissue as their own.

Stem cell research still has some hurdles to clear before iPSCs are ready for clinical treatments. The creation of iPSCs is based on “unpacking” genes—the parts of DNA that regulate cell function—to allow reversion to a stem cell state. When hESCs differentiate, the genes that are no longer needed are packed by proteins called histones, which can prevent those genes from being accessed. Scientists refer to these packaging patterns as chromatin marks; so far, the chromatin marks of iPSCs are distinct from the original cell and the cell they ultimately differentiate into, as well as hESCs. The concern is that there may be genes available for expression in iPSCs that should be dormant. Having genes aberrantly expressed in stem cells could cause diseases, including cancer.

If iPSC-derived MSCs pose any risk, limiting their ability to travel in the body will be imperative. This is one of the reasons why The Maverakis Lab is working on hydrogel delivery of MSCs. Hydrogels are gelatinous matrices that can provide an environment for MSCs to develop within. The hydrogel has small molecules attached to the matrix that bind the MSCs and cause them to release factors that encourage growth and healing in the surrounding tissue. Not only does the hydrogel provide important stimulus for the MSCs, but it can also localize MSCs to the wound site.

Stem cells offer the promise of personalized medicine: tissue repair without rejection, drug screening to provide accurate dosing and effective medicines with fewer side effects, and custom treatments for diverse cancers. Whether due to advances in stem cell research or for self-preservation in the face of aging, public sentiment has shifted. The last study from Virginia Commonwealth University indicated majority support (62%) even for research on hESCs5. Although scientists have discovered many facets of stem cell biology, there is still a veritable treasure trove of opportunities that will undoubtedly improve our ability to treat disease.

References

1Funk, Carey. “VCU LIFE SCIENCES SURVEY.” 2002. PDF file. Web. 11 Mar. 2016. http://lifesciences.vcu.edu/media/life-sciences/docs/survey2002.pdf

2Sen, Chandan K. et al. “Human Skin Wounds: A Major and Snowballing Threat to Public Health and the Economy.” Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society 17.6 (2009): 763–771. PMC. Web. 11 Mar. 2016.

3Guerra, Alberto Daniel et al. “Mesenchymal Stromal/Stem Cell and Minocycline-Loaded Hydrogels Inhibit the Growth of Staphylococcus Aureus That Evades Immunomodulation of Blood-Derived Leukocytes.” The AAPS Journal 17.3 (2015): 620–630. PMC. Web. 11 Mar. 2016.

4Takahashi, Kazutoshi and Shinya Yamanaka. “Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.” Cell 126.4 (2005): 663-676. CellPress. Web 11 Mar. 2016.

5Funk, Carey. “VCU LIFE SCIENCES SURVEY 2010.” 2010. PDF file. Web. 11 Mar. 2016. http://lifesciences.vcu.edu/media/life-sciences/docs/survey2010.pdf

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The Challenges and Benefits of Using Stem Cells in Psychiatry

Jessica PalkaBy Jessica Palka

Ongoing research involving stem cell-based interventions for mental illness may have the potential to provide improved treatments or even cures for depression, schizophrenia, and bipolar disorder.  In their quest to understand what is going wrong in the brain cells of affected patients, researchers are examining the molecular causes of these disorders to determine if stem cell-based treatments may be used to replenish degenerated brain tissue in patients. The excitement in the field is palpable given the deficit of effective treatments for those suffering with severe mental illness.

The development of treatments for psychiatric diseases has been hampered by difficulties in understanding their underlying causes, which seem to vary wildly. For example, it is not clear whether some mental illnesses begin during embryonic development or develop much later in life. There is significant data suggesting that many mental illnesses are caused by developmental abnormalities of the brain before birth, but other studies indicate that some mental illnesses may be caused by the destruction of adult brain tissues (Benninghoff, 2009). Of course, these scenarios are not mutually exclusive; mental illness can have developmental origins and also involve brain degeneration later in life. Determining when these conditions develop will potentially help scientists and clinicians detect and prevent these illnesses. Many scientists are hopeful that stem cells might be used to reverse the events that lead to the disease. If an illness is caused by or leads to degeneration and loss of brain cells, could stem cells be used to produce new cells in the brain?Palka Brain sketch

Interestingly, it may be that not only can nervous tissue degeneration lead to psychiatric conditions, but also that the latter can cause the former. A study of individuals suffering from major depression provides evidence that depressive episodes can trigger degeneration of tissues in the adult nervous system (Stratmann et al., 2014). The individuals examined in the study suffered from a loss of total cell volume in certain brain areas (Benninghoff, 2009). If this result is found to be consistent in future studies, it could mean major depression would be categorized as a neurodegenerative condition. In this context, stem cells might be used to heal the brain damage inflicted by this mental illness.

Scientists investigating the use of stem cells for treatment of major depression (or other psychiatric disorders) might benefit from learning about the challenges faced when treating more classical neurodegenerative diseases. In cases with stem-cell based interventions for neurodegenerative diseases like Duchenne’s disease, Parkinson’s disease, and Alzheimer’s disease, there are ongoing discussions about which stem cell type (embryonic, fetal, or adult) is more appropriate for production of neural progenitor cells (Benninghoff, 2009). The progenitor cell is a kind of intermediate or “teenage phase” that differntiating stem cells go through as they develop into adult cell types. By using neural progenitor cells in their research, scientists can be sure the cells will ultimately develop into neurons rather than skin, muscle, or any other kind of cells.

Trafficking stem cells or progenitor cells to the appropriate location (a process known as stem cell homing) presents another challenge (Benninghoff, 2009). Surgical transplantation of stem cells to a specific area is effective but invasive. Instead, it may be possible to inject stem cells and allow the cells to travel within the circulatory system to the brain where they would home to the appropriate region based on complex molecular and cellular interactions (Benninghoff, 2009). This would allow injection of cells into most any vein, such as the easily accessible median cubital vein in the forearm (from which blood is commonly drawn) (Benninghoff, 2009).

Apart from the technical issues, ethical problems also are ever present when it comes to stem cell research. Controversy will likely always surround the use of human embryonic stem cells. However, this debate has become less relevant thanks to the advent of a process in 2006 that allows scientists to create cells that behave like embryonic stem cells from any adult cell type (for example, a skin cell could be turned into an embryonic stem cell-like cell) (Takahasi & Yamanaka, 2006). These cells, called induced pluripotent stem cells, are reducing the necessity of using human embryonic stem cells in medical research and opening up exciting new options in terms of using stem cells for therapeutic purposes.

Stem cells could offer a much-needed alternative to the pharmacological treatment of mental disorders. Using prescribed medications for mental disorders is problematic since it necessitates patient compliance to a strict schedule of medications (Benninghoff, 2009). This is further complicated by the unfortunate reality that many medications cause undesirable side effects, including changes in appetite, fatigue, nausea, heart problems, general malaise, and sometimes even an increased risk of suicide. Stem cell-based treatments for mental illness may help provide a better alternative to drug compounds for those suffering with mental illness.

As more research is being done in the stem cell field, there is an ever-increasing likelihood that stem cells will be used in the treatment of psychiatric illnesses. Although there are many challenges yet to overcome, the potential benefits of using stem cells to restore proper brain functionality for the millions of people suffering from mental illness offers an incentive that is impossible for the scientific community to ignore.

References

Benninghoff, J. (2009). Stem cell approaches in psychiatry - challenges and opportunities. Dialogues in Clinical Neuroscience11(4), 397–404.

Bhasin, A., Padma Srivastava, M.V., Mohanty, S., Bhatia, R., Kumaran, S. S., & Bose, S. (2012). Stem cell therapy: a clinical trial of stroke. Clinical Neurology and Neurosurgery, 115. 1103-1108.

Stratmann, M., Konrad, C., Kugel, H., Krug, A., Schöning, S., Ohrmann, P., … Dannlowski, U. (2014). Insular and Hippocampal Gray Matter Volume Reductions in Patients with Major Depressive Disorder. PLoS ONE9(7), e102692. http://doi.org/10.1371/journal.pone.0102692

Takahasi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4), 663-676. doi:10.1016/j.cell.2006.07.024

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