Let's Talk About Stem Cells!

by Ellen Mintz

         It's early Friday morning, and still dark and cold, the time of morning when only some animals are active and humans are all still sleeping.  I have my gear loaded in the car, and am ready to get to work. I am not going out into the field to catch kangaroo rats, catch fish, or track rattlesnakes (although those all sound like fun projects!).  My gear is a pen, notebook, and collection of research abstracts, and I am headed down to a meeting in the sunny beach town of La Jolla, CA, where some of the most innovative and cutting edge research in stem cell biology is taking place at research institutions like The Salk Institute, The Scripps Research Institute, and UC San Diego.  The amazing applications of this research could improve the lives of many and result in hundreds of applications in science and medicine.

The Salk Institute in La Jolla
http://www.galinsky.com/buildings/salk/

Stem Cell Basics

            Stem cells are unique cells located in special places around the body that can differentiate into specialized cells or self renew and become more stem cells.  They are influenced to change by their environment, which includes other cells and factors released by those cells and by the stem cells themselves.  The ultimate stem cells of the body, eggs and sperm, are referred to as totipotent, meaning they can differentiate into any tissue type in the body.  Pluripotent stem cells have the ability to differentiate into any of the three tissue types in the body: mesoderm, endoderm, or ectoderm.  A neural progenitor cell is an example of a multipotent stem cell; it has the ability to differentiate into neurons or glial cells.  Stem cells can also be unipotent, meaning they are the direct precursors to a specific cell type.

Stem Cell Differentiation
http://www.scq.ubc.ca/wp-content/uploads/2006/07/stemcells2-GIF.gif

           The gold standard of stem cells are human embryonic stem cells (ESCs), obtained from the inner cell mass of a four day old blastocyst (post fertilization ball of cells).  These totipotent cells can be induced to become any tissue type, and are easily obtained from IVF clinics.  However, some people have ethical concerns over their use.  In 2006, a method was developed to reprogram mature adult cells back into a pluripotent state, similar to embryonic stem cells! This technique won Shinya Yamanaka and Sir John Gurdon the Nobel Prize in Science and Medicine this year, something that definitely has huge prospects for regenerative medicine, cell therapies, and studying how different diseases develop.

            Stem cells are cultured, or grown, flat in dishes or allowed to form spheres, mimicking the environment that they are naturally found in the body and surrounded by growth and differentiation factors.  These cells can then be used in cell therapies to treat many different diseases and conditions, a really exciting prospect for regenerative medicine! Let’s look at some of the diseases that have the potential to be treated or cured eventually using stem cells.

Sir John Gurdon, 2012 Nobel Prize Winner

http://www.ox.ac.uk/media/news_stories/2012/121008.html

Shinya Yamanka, 2012 Nobel Prize Winner

http://gladstoneinstitutes.org/nobel/media.html

Parkinson’s Disease

Parkinson’s disease is a neurodegenerative disorder caused by a loss of dopaminergic neurons (neurons that release dopamine as a neurotransmitter) in the brain, in an area called the substantia nigra.  It is one of the most common nervous system disorders in the elderly, and exhibits symptoms such as muscle rigidity and tremors, stooped posture, movement problems, and issues with balance and walking.

The brain affected by PD

http://www.umm.edu/patiented/articles/what_parkinsons

_disease_what_causes_it_000051_1.htm

            Current treatments of Parkinson’s disease include administration of L-DOPA (the precursor to dopamine), the implantation of fetal dopaminergic neurons into the brain, and deep brain stimulation by electrical activity (see my last blog for more information on this!).  Unfortunately, these treatments only provide temporary relief of PD symptoms, and fetal dopaminergic neurons are difficult to obtain and add a whole other dimension of ethical issues with their use.

Cynomolgus Monkey

http://topics.time.com/thailand/pictures/

            For those of you who did not just take your Bio 502 oral exam, dopamine is created in neurons when tyrosine (an amino acid) is converted to L-DOPA by the enzyme tyrosine hydroxylase (TH), and is then acted upon again by the enzyme amino acid decarboxylase to produce the final product.  A common way to look for dopaminergic neurons in the brain is to look for the presence of TH in neurons.

            Takagi et al. (2005) used primate ESCs and differentiated them into progenitors of dopaminergic neurons, then treated them with factors that would allow them to remain differentiated.  These neurons were then transplanted into cynomolgus monkeys that were treated with 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (Try saying that five times fast! We’ll just call it MPTP), which is used to induce PD in animal models.  Following transplantation, these neurons were still functional in their dopaminergic activity by releasing dopamine, and were actually able to diminish PD symptoms in the monkeys!

Stained dopaminergic neurons from Takagi et al (2005)

Heart Attack and Cardiac Function

            In 2012, a clinical trial called CADUCEUS (full name: CArdiosphere-Derived aUtologous stem Cells to reverse ventricular dysfunction) treated patients who had suffered a myocardial infarction, or heart attack, with stem cells and looked to see how it affected the damaged heart tissue.

Naming clinical trials

http://www.phdcomics.com/comics/archive.php?comicid=1100

            A heart attack is caused by a lack of oxygenated blood flow to the heart.  Because there is no oxygen being delivered to the tissue, the muscle tissue of the heart (the myocardium) cannot pump like it should and begins to die.  Despite treatment following a heart attack, patients often develop scarring in place of healthy heart tissue, which results in reduced function, further heart failure, or even death.  Therapies aim to decrease this scarring, and instead rebuild the heart with healthy tissue.  While this has been somewhat effective, the treatment does not always work equally well in all cases, and does not always last as long as desired.

Damaged heart tissue following myocardial infarction

http://nursing-care-plan.blogspot.com/2011/12/

myocardial-infarction-pathophysiology.html

            The clinical trial resulted in an overall increase in viable, healthy heart tissue when the patients were looked at collectively, and demonstrated that the special stem cells that the researchers used (derived from a cardiosphere) were able to not just reduce the amount of scar tissue but also stimulate the regrowth of healthy myocardium.  This is promising, but the next step would be to look at the function of this tissue and the heart overall following a stem cell therapy.

Diabetes

            Type II Diabetes is a disease that is characterized by high blood glucose levels, usually resulting from a resistance to insulin or a lack of insulin production.  Insulin is a hormone produced by special cells (the islet cells) in the pancreas that causes an uptake of glucose by tissues such fat, liver, and muscles.  When cells do not respond to insulin, glucose from the meal you just consumed continues to circulate in your blood, leading to problems such as slowly healing infections, blurred vision, fatigue, pain and numbness in the extremities, and eventual eye, kidney, and cardiovascular disease.  Family history and genetic factors play a role in the development of Type II Diabetes, and unhealthy lifestyle choices involving poor diet and lack of exercise only exacerbate the problem.  The best cell therapy to treat Type II Diabetes is islet cell transplantation, however there is a high cost associated with this as well as probable negative immune reactions.

Insulin producing islet cells in the pancreas
http://stemcells.nih.gov/info/scireport/pages/chapter7.aspx

            Human mesenchymal stem cells are found most commonly in the bone marrow, but also in certain fetal tissues like the umbilical cord, placenta, and fetal lung.  Mesenchymal stem cells (MSCs) are cool because they secrete important molecules that cause growth throughout the body, and regulate the creation of blood cells (hematopoiesis), the creation of new blood vessels (angiogenesis), and immune and inflammatory responses.  As it turns out, MSCs have the ability to differentiate into pancreatic islet cells!  The placenta is an ideal place to obtain these cells because it is usually discarded as a waste product following birth, it does not cause as strong of an immune response in patients, and there is an extremely decreased amount of ethical concern with its use.

            Jiang et al (2011) transplanted placental MSCs into ten patients with Type II Diabetes who had insulin dysfunction and poorly controlled blood glucose levels, as well as coronary artery disease, kidney disease, atherosclerosis, and large limb neuropathy.  The patients received the transplant and continued to inject insulin as well, however this was controlled for in the results by measuring the presence of c-peptide, a molecule cleaved from the insulin precursor proinsulin to make insulin.  There were no obvious negative side effects to the transplantation, and C-peptide levels were significantly elevated, meaning the islets were working and creating insulin!  The MSCs were able to differentiate and function as islet cells!

Current Challenges and Future Directions

Cool fluorescent stem cell
http://youreyesite.net/2010/06/08/stem-
cell-treatment-for-macular-degeneration-in-germany/

            Stem cell research is exciting, but there is still a lot of work left to do before they are a viable treatment option for human use.  Some challenges left to overcome include where we get the stem cells from, how to differentiate them and keep them in that differentiated state, and what factors affect how they behave.  It is important to remember that animal models can only go so far; inducing diseases in animals models only one aspect of a pathology that may be caused by many complex factors. For example, the MPTP monkey models the cause of PD, but does not experience the progressive degeneration that the disease actually causes.  There are also ethical issues, especially pertaining to ESCs, and safety issues with implanting stem cells into animals and their tendency to form tumors.  Most stem cell clinical trials are able to determine that the treatment is safe, but cannot make a determination about the effectiveness at this time.  The biology of stem cells and how they behave in the body as a whole is a rapidly growing field, growing in leaps and bounds every year! New discoveries are being made every day, with novel ideas for the use of stem cells.

            Keep an ear out for stem cells in the news, and an eye on these blogs for more stem cell biology from one of my CIRM Bridges program peers…

For more information…

            The California Institute for Regenerative Medicine funds stem cell research involving hESCs in particular.

            http://www.cirm.ca.gov/

            To see how stem cells are being studied at Cal Poly, check out the link for the CIRM Bridges MS Specialization in Stem Cell Research at Cal Poly!

            http://cirm.calpoly.edu/

Special thanks to the half of the CIRM Bridges program students in my car for all their feedback!

References

Jiang, R., Z. Han, G. Zhuo, X. Qu, et al. 2011. Transplantation of placenta-derived mesenchymal stem cells in type 2 diabetes: a pilot study. Frontiers of Medicine 5(1): 94-100.

Makkar, R., R. Smith, K. Cheng, K. Malliaras, L. Thomson, et al. 2012. Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomized phase 1 trial.  The Lancet 379:895-904.

"Parkinson's Disease." PubMed Health. PubMed, 26 Sept 2011. Web. 15 Feb 2013. <http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001762/>.

Stem Cell Basics. In Stem Cell Information. Bethesda, MD: National Institutes of Health, U.S. Department of Health and Human Services, 2009 [cited Friday, February 15, 2013. http://stemcells.nih.gov/info/basics/Pages/Default.aspx

Takagi, Y., J. Takahashi, H. Saiki, A. Morizane, et al. 2005. Dopaminergic neurons generated from monkey embryonic stem cells function in a Parkinson primate model. The Journal of Clinical Investigation 115(1):102-109.

"The 2012 Nobel Prize in Physiology or Medicine - Press Release". Nobelprize.org. 15 Feb 2013 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2012/press.html

"Type II Diabetes." PubMed Health. PubMed, 28 June 2011. Web. 15 Feb 2013. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001356/