Stem Cells: Their Properties and Use in Neuroregenerative Therapies. Benjamin Angeles

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1 Stem Cells: Their Properties and Use in Neuroregenerative Therapies Benjamin Angeles Independent Study Mrs. Graves June 3, 2016

2 WHAT I KNEW/WANTED TO KNOW Preceding my initial research, I knew very little about this topic. But I could name out a few facts like that stem cells can be used to make tissue for the body, and some are found in babies still in the womb. Stem cells are like brain cells and cannot normally divide through the cell cycle. Although I had sparse knowledge about this topic, it helped spark more interest about this exciting and expanding field of research, and I easily formed several inquiry questions that I wanted to focus on. My preliminary research included research about what stem cells actually are, where they are located, and how are they being utilized in medical treatments presently. After I finished that I delved deeper into the world of stem cell research and I wanted to find out the mechanics of stem cells: how do they work, how are they produced, and how they can be used to treat damaged, irreparable cells like brain and nerve cells. My final question was what the future outlook was for stem cell research and its use in the medical field knowing that this flourishing field would be beneficial to a growing population susceptible to diseases like diabetes and PSP which will be discussed later. THE SEARCH Growing up, I've always wanted to be in the medical field (not because my parents said I needed to be a doctor or anything), and I had wanted to be a pediatrician for the longest time. But throughout the last few months, I think I've drawn away from interacting with patients, and I've become interested in working in a research lab as a biomedical engineer. My older cousin, Olivia, is now working on her PhD in this field, and she works in a lab at Mount Sinai Hospital

3 in New York. She was one of the first people to inform me about biomedical engineering. The branch of study in this field that I want to pursue is research about stem cells. My search started with a trip to the library with my English class in April. With the meager knowledge I had about stem cells, I first needed to get the fundamentals. One of the librarians had informed our class about Google Scholar, so I went there first to see if I could gather any information about stem cells that I could understand. To my dismay, most of the sources were too difficult for me to understand because of all the medical terminology and concepts that went over my head. Although I found much of the information I could understand pretty interesting, I decided to use just good old Google Search to start off, and to try Google Scholar later in my research. One of the best things I remember while I was exploring the different sites was when I found the source with all the information that I needed for the basics named simply, Stem Cell Basics, and it was created by the National Institute of Health (NIH) so it was an awesome find! One of the great things about this website was that it included several subsections of information like What are the unique properties of stem cells? and What are the similarities and differences between embryonic and adult stem cells?. The site even had a glossary of key terms associated with stem cells! This one website was the holy grail per say for the fundamentals I needed for a good foundation in deciphering the medical vocabulary of the more sophisticated sources. Although I will not go in detail about all my research (I ll do that in the next section!), I ll give a brief overview of what I found. During my background research I learned about the two different types of stem cells, adult/somatic and embryonic and the varying characteristics of each. I found it really interesting how science has progressed through a short span of time and that scientists were able to discover so much about stem cells. Thinking of the technology we

4 have now, I can imagine that we will be using stem cells in regenerative therapies very soon, and as the title of my Isearch paper implies, I did some research about neuroregenerative therapies, specifically about Progressive Supranuclear Palsy (PSP). I researched this topic because my grandmother passed away due to PSP. I couldn't really understand why she was sick back then because I was so young, but now I want to know what the pathology of the disease was. Finding several sources of information about PSP has helped me understand more what my grandmother was going through, and seeing that there are possible treatments using stem cells brings hope for more effective regenerative treatments in the future. Hopefully I get to take part in the process. THE RESULTS What are stem cells? This question was proposed in the early 1950s when stem cells were first discovered in the bone marrow which houses hematopoietic stem cells which form all blood cell types and bone marrow stromal stem cells which form bone, cartilage, and stromal cells. This later led to a concrete definition: they are cells that are able to develop into different types of cells where they can act like a "repair system", can essentially divide without limit, and after they divide, they can stay as a stem cell or become a specialized cell. 4 Two distinguishing characteristics are that stem cells are unspecialized, meaning that they serve no specific purpose in the body and can renew themselves through cell division. Under certain conditions, they can be induced to become tissue which will be discussed later. There are two major types of stem cells: Embryonic stem cells and somatic/"adult" stem cells. Embryonic stem cells are from embryos and can be derived from eggs that have been fertilized in vitro (outside of the normal environment). Somatic stem cells, the ones discovered in the 1950s,

5 generate cell types of the tissue in which they reside (ie: stem cells in bone marrow produce blood cells; "hematopoietic" stem cells). Embryonic stem cells are pluripotent meaning they have the ability to give rise to all of the various cell types of the body. Human embryonic Stem Cells (hescs) are derived from in vitro fertilization during preimplementation when the embryo has not been attached/implemented itself into the uterus of a woman. Pluripotency of a stem cell is tested by scientists by providing evidence of stable developmental potential to form derivatives of all three embryonic germ layers: (from outermost to innermost) ectoderm, mesoderm, and endoderm where each layer gives rise to certain tissue and organs in later development of an embryo. In the lab, embryonic stem cells are grown in vitro where they absorb nutrients through a culture medium. Normally, if a culture lasts 6-more months without differentiating, then the stem cells are pluripotent and genetically normal, so this creates a embryonic stem cell line. Embryonic stem cells can spontaneously differentiate by clumping and forming embryoid bodies which are clumps of stem cells that contain cell types from all germ layers. However, this is an inefficient way of production because it is uncontrolled. Controlled differentiation can be achieved by changing the chemical composition of the culture medium, altering the surface of the culture dish, or adding specific genes to modify the cells. Scientists subculture embryonic stem cells for several months to ensure that they are capable of self-renewal and long-term growth with the use of specific techniques, indication of two important transcription factors (Nanog and Oct4) and determination of the presence or lack of markers on the cell surface. These transcription factors and markers keep the cell in an undifferentiated state. 5 Scientists also test embryonic stem cells by examining the chromosomes under a microscope to determine if they are damaged or if there is the right number.

6 Somatic stem cells are also undifferentiated, but are found in tissue and organs in areas called, "stem cell niches". They differentiate to form the cell type of where they are located (ie. stem cells in the bone marrow create blood cells) and are used to repair and maintain tissue/organs, as stated previously. Continued research has led to new discoveries on where somatic stem cells reside, for example, in the 1960s they located a stem cell niche in the brain that can generate astrocytes, oligodendrocytes, and neurons. 5 A downside to somatic (and embryonic for that matter) stem cells is that there are only a small number of them in each tissue, and with somatic stem cells, their capacity to divide lowers when removed from their niche. There are also tests for somatic cells that include labeling them with molecular markers to determine what cell types they generate, and removing cells, labeling them, and then transplanting them back to see if they repopulate their respective tissue origin. Looking to the future, stem cells in general will help scientists better understand the events in early human development, how undifferentiated cells become the differentiated cells that form tissues of organs, and will aid researchers in comprehending the abnormal cell division and differentiation of diseases like cancer and birth defects to help them create new treatment possibilities. Further studies on how to safely induce cells and control them must be done to comprehend the signals that control differentiation because scientists are still unsure of their true purposes. As stated earlier, PSP stands for progressive supranuclear palsy. Scientists do not waste words in their nomenclature, so there is a meaning behind the choice of words for this disease s name. Progressive is used because the disease worsens over time. Supranuclear means it damages certain parts of the brain above nerve cell clusters, the nuclei. And palsy to describe that it weakens the body. 2 Although the etiology, which is the "cause, set of causes, or manner of

7 causation of a disease or condition," is unknown, PSP is a tauopathy where from a pathological point of view; is part of a group of disorders that have an accumulation of the tau protein in areas of the brain stem, cerebral cortex and the cerebellum that cause a neurodegenerative process. 2 Tau protiens are supposed to stabilize microtubules in the cytoplasm and they are abundant in the neurons. Misfolding/denaturing of the protein is most likely due to genetic mutation and/or exposure to environmental factors. 2.3 Symptoms of PSP include loss of balance when walking, blurred vision and slow eye movement, but the key sign of the disease is the paralysis of the vertical gaze (and then later the horizontal gaze). This symptom is what sets it apart from other parkinsonisms along with differences. PSP is more rapidly progressive than Parkinson s disease. People with PSP tend to stand really straight and lean backwards and fall early on. This is called, axial rigidity. However, people with Parkinson's tend to fall forward. People diagnosed with PSP tend to have more abnormal eye movements. PSP is linked to high accumulation of the tau protein whereas Parkinson's is associated with buildups of the alpha-synuclein protein. Currently there are no treatment options that can prevent PSP, but there are therapies that can facilitate it in the patient. 3 The neurodegeneration process of PSP that destroys the parts of the brain has been recently studied by several scientists and doctors. With the use of mesenchymal stem cells (MSCs) which are pluripotent and somatic and can be isolated from several areas in the body like bone marrow, the investigators have devised a design to treat PSP. These MSCs have the potential to transdifferentiate where stem cells from one tissue differentiate into cells of another tissue (ie. blood cells in bone marrow to brain cells in neurons). The treatment of PSP by MSCs involves the lowering of oxidative stress on the neurons which helps maintain the cell s homeostasis, regulations in cell differentiation, and reducing of cell apoptosis or programmed

8 cell suicide. After analysis of the data, the study has claimed to be statistically significant since the p value of their test was less than the alpha value. Although the MSCs do not replace the neuronal cells, they exert a sort of neuroprotective role in the brain. 1 MY GROWTH AS A RESEARCHER Throughout this researching process, I believe I have grown somewhat over the past few months and have become a better researcher. I learned the hard way that I need to plan out my time better to delineate when I will do what because I was a little unorganized. I was also supposed to interview a professional, but I never got to because of poor timing. Overall, I have learned from my mistakes (hopefully) and I think this experience has prepared me well for my senior project. I hope to continue my research on stem cells for a possible senior project, and maybe when I'm in college. This topic as allowed me to see a different side of the medical field that I had not really delved into: biotechnology. With the growing need for new therapies for diseases, biotechnology offers a different perspective at tackling these problems. My research has led to become interested in this filed of research, and I can't wait to see where i

9 Cited References 1. Giordano, R., Canesi, M., Isalberti, M., Isaias, I. U., Montemurro, T., Viganò, M., Pezzoli, G. (2014, January 17). Autologous mesenchymal stem cell therapy for progressive supranuclear palsy: Translation into a phase I controlled, randomized clinical study. Retrieved April/May,2016, from 2. Progressive Supranuclear Palsy Fact Sheet. (2015, September). Retrieved April/May, 2016, from 3. Tau protein. (n.d.). Retrieved April/May, 2016, from 4. Stem cells: Research milestones and more. (n.d.). Retrieved April/May, 2016, from 5. Stem Cell Basics. (2015). Retrieved April/May, 2016, from