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Stem Cells

Stem Cells

*Dr. Kalpana Mujoo

Research work with stem cells

I have been involved in biomedical research for more than 20 years. However, I started working with stem cells approximately three and a half years ago. It is an exciting yet challenging area of research. Our primary goal in the laboratory is to determine how undifferentiated (unspecialized) stem cells can be differentiated into more specialized cells such as heart cells and the molecular events leading to this switch. There are many different types of signaling pathways that are involved in either maintaining the stem cells in the undifferentiated stage or are involved in differentiating stem cells into various lineages. We are conducting research on one such signaling pathway � the Nitric Oxide pathway. Nitric Oxide (NO) is a colorless, odorless gas and an uncharged free radical that is involved in number of physiological processes such as smooth muscle relaxation, neurotransmission, inhibition of platelet aggregation and host defense mechanisms. The overall goal of our project is study the role of Nitric Oxide-cGMP pathway in proliferation and differentiation of stem cells into cells of various lineages such as myocardial cells (heart cells).

At the present time, we are using cocktails of various agents to differentiate the undifferentiated cells into myocardial cells for future regenerative medicine for diseases such as myocardial infarction (heart attack). I have honor and privilege to conduct these studies with Dr. Ferid Murad, M.D., Ph.D. 1998 Nobel Laureate in Physiology or Medicine, who is a Director Emeritus and Director of Cell Signaling Center at the Institute of Molecular Medicine. Dr. Murad discovered the mechanism of action of nitroglycerine, a drug that has been used in clinic for more than 100 years for chest pain (angina pectoris).

The most exciting part of the research is in unraveling the mysteries of unknown and the most gratifying part of the research is to see its impact in the treatment or quality of life of patients with different diseases.

To understand more about our work with stem cells, let me start off by explaining some basic facts about stem cells.

What are stem cells?
Stem cells are the founder cells in the body. They are unspecialized (undifferentiated) cells with some unique properties: 1) they can self-renew which means that they have potential to give rise to unaltered daughter cells by cell division 2) they can give rise to specialized cells (differentiated cells) such as beating cells of the heart or insulin producing cells of the pancreas under appropriate experimental conditions

What are different types of stem cells?
There are many different types of stem cells:
Adult stem cells: the undifferentiated cells found within the differentiated cells of the tissue or organ. Adult stem cells are also called tissue-specific stem cells. Their primary role is to maintain and repair the tissue or organ in which they reside. Their origin in the adult tissue is unknown at the present. Adult stem cells have been isolated from many tissues of the body including the brain and heart. The most common source of adult stem cells is bone marrow. There are many different types of adult stem cells in bone marrow: a) hematopoietic or blood stem cells which give rise to all the cells of blood b) endothelial stem cells which form arteries and veins c) mesenchymal stem cells which form bone, muscle, fat, cartilage and fibroblast. Adult stem cells have also been isolated from the cord blood of newborn babies and this is currently an active area of research. Recently, stem cells have been shown to exist in amniotic fluid and baby teeth as well. A number of studies have suggested that some adult stem cells have potential of transdifferentiation, which means that these cells have ability to differentiate into multiple cell types of different tissues. For example, stem cells from bone marrow can differentiate into liver cell, heart cells and cells of other organs.

Embryonic stem cells (ESC): ES cells are derived from the inner cell mass of the pre-implantation embryo. They have the capacity to self renew for prolonged periods of time under appropriate culture conditions. ESC are pluripotent which means that these cells have potential to make cells of all three germ layers ectoderm (outermost germ layer of cells derived from inner cell mass of blastocyst, which gives rise to nervous system, skin, sensory organs and related structures), mesoderm (middle layer of the group of cells from inner cell mass of the blastocyst; it gives rise to bone, muscle, connective tissue, kidneys), and endoderm (inner most layer of the cells which give rise to lungs, other respiratory structures and digestive organs). In other words, ES cells have potential to make many cells of the body such as neural progenitors, cardiomyocytes (heart cells), hepatocyte like cells (liver cells), osteoblasts (bone cells), hematopoetic lineages (blood cells), and insulin-expressing cells. Therefore, due of these unique characteristics, embryonic stem cells hold a great promise in the field of regenerative medicine and other important applications.

Similarity and differences between embryonic and adult stem cells
There are potential advantages and disadvantages with both adult and the embryonic stem cells for their use in cell-based therapy.

ES cells are pluripotent (ability to differentiate into almost every cell of the body) and these cells can self-renew meaning they can be grown for prolonged periods of time whereas adult stem cells have limited differentiation potential (multipotent) and these cells cannot be grown in large quantities for prolonged period of time. However, adult stem cells can be derived from the patient�s own cells and grown in the tissue culture and reintroduced into the patient, which would avoid their rejection by the immune system. ES cells on the other hand, could have potential immune rejection problems, though such studies have yet to be conducted in human experiments. In addition, ES can form teratomas (tumors with cells of all three germ layers) and therefore their efficacy and safety needs careful evaluation.

Potential use of stem cells in cell based therapies:
The process in which the healthy cells replace the damaged cells is known as the process of cell-based therapy. Transplantation of stem cells in any degenerative diseases (such as stroke, spinal cord injury, heart disease, muscular dystrophy, Parkinson disease and others) holds great promise in the field of regenerative medicine. However, in spite of the promising results in the animal models of some of the diseases (for example Parkinson disease model, coronary ligation model for heart attack), the use of stem cells and their use in various human diseases are still at a very preliminary stage.

Hemeatopoetic stem cells (blood stem cells) are the precursor cells for all the blood cells. These stem cells are the only type of stem cells currently used for cell-based therapy in humans. Advanced techniques are currently being used to collect blood stem cells from bone-marrow (doctors have used bone-marrow transplant for last 40 years) for the treatment of leukemia, lymphoma and other inherited blood disorders.

For a comprehensive review of stem cells, please go to National Institutes of Health website www.nih.gov, and click on the link about stem cells.
International Society for Stem Cell Research: www.isscr.org

What are the qualities required to be a researcher: Utmost curiosity to unravel the unknown. At the same time, you must have enough patience to see the project through and willingness to work long and hard hours to achieve the goals.

Advice or Mantra for aspiring researchers: Patience, hardwork, and dedication.

*Kalpana (Mujoo) Singh, PhD is a faculty member at the Brown Foundation Institute of Molecular Medicine for the prevention of human diseases and an adjunct faculty member of the Department of Integrative Biology and Pharmacology at the UT Health Science Center at Houston. Kalpana received her undergraduate and Masters degrees from Lucknow University and her doctoral degree in Biochemistry at the Central Drug Research Institute in India. She pursued her postdoctoral training at the Scripps Research Institute in La Jolla, CA, in the area of Biochemistry, Cancer Biology and Tumor Immunology. During her postdoctoral training she developed a number of monoclonal antibodies against well-characterized tumor associated antigens and one such antibody has been used in multi-center clinical trials for human neuroblastoma (child hood brain tumor) and melanoma (skin cancer) in the USA and Germany. During her term at the University of Texas M.D. Anderson Cancer Center, Dr. Mujoo was involved in conducting research in basic cancer biology and experimental therapeutics area. She focused her efforts in elucidating the molecular mechanisms of various anti-cancer agents and studying their therapeutic potential in various cancer models.

Her current research focuses on delineating the role of nitric oxide (NO), a colorless, odorless gas and cyclic GMP (second messenger) signaling in proliferation, differentiation, and self-renewal of mouse and human embryonic stem cells and adult stem cells. In addition, she is interested in elucidating the role of NO signaling pathway in various human cancers. Dr. Mujoo is a member of International Society of Stem Cell Research and American Association for Advancement of Sciences. She has also been a past member of the American Association for Cancer Research.

Kalpana was born in Srinagar, Kashmir and brought up in Lucknow, where her father was a university Professor. She is married to Dr. Balraj Singh who received his Ph.D. in Life Sciences from JNU, New Delhi. She is a mother of two teenage boys (19 and 14) and is blessed with wonderful family and friends who have touched her life in many ways.

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