INTRODUCTION TO STEM CELL TECHNOLOGY

INTRODUCTION TO STEM CELL TECHNOLOGY
Hariom Yadav1, Shalini Jain1 and Mukesh Yadav2 1nimal Biochemistry Division, National Dairy Research Institute, Karnal , Haryana, INDIA 2SOS in Chemistry, Jiwaji University, Gwalior , M.P., INDIA Corresponding author:

Importance of Stem Cell Research
5/4/2018 Dr. Hariom Yadav

Stem Cell History Researchers first extract stem cells from human embryos First Successful human transplant of insulin-making cells from cadavers President Bush restricts federal funding for embryonic stem-cell research Juvenile Diabetes Research Foundation International creates $20 million fund-raising effort to support stem-cell research California ok stem cell research Harvard researchers grow stem cells from embryos using private funding Ballot measure for $3 Billion bond for stem cells 5/4/2018 Dr. Hariom Yadav

Stem Cell – Definition A cell that has the ability to continuously divide and differentiate (develop) into various other kind(s) of cells/tissues Stem cells are different from other cells of the body in that they have the ability to differentiate into other cell/tissue types. This ability allows them to replace cells that have died. With this ability, they have been used to replace defective cells/tissues in patients who have certain diseases or defects. 5/4/2018 Dr. Hariom Yadav

Stem Cell Characteristics
‘Blank cells’ (unspecialized) Capable of dividing and renewing themselves for long periods of time (proliferation and renewal) Have the potential to give rise to specialized cell types (differentiation) Common variants, called polymorphisms, occur at greater than 1% frequency I have given some examples of how exposure induced risk is modified in various ways Typically the effects are modest in magnitude. We are interested in how genetics modifies Exposure and exposure-related diseases Because….. 5/4/2018 Dr. Hariom Yadav

Kinds of Stem Cells Stem cell type Description Examples Totipotent
Each cell can develop into a new individual Cells from early (1-3 days) embryos Pluripotent Cells can form any (over 200) cell types Some cells of blastocyst (5 to 14 days) Multipotent Cells differentiated, but can form a number of other tissues Fetal tissue, cord blood, and adult stem cells Stem cells can be classified into three broad categories, based on their ability to differentiate. Totipotent stem cells are found only in early embryos. Each cell can form a complete organism (e.g., identical twins). Pluripotent stem cells exist in the undifferentiated inner cell mass of the blastocyst and can form any of the over 200 different cell types found in the body. Multipotent stem cells are derived from fetal tissue, cord blood and adult stem cells. Although their ability to differentiate is more limited than pluripotent stem cells, they already have a track record of success in cell-based therapies. Here is a current list of the sources of stem cells: Embryonic stem cells - are harvested from the inner cell mass of the blastocyst seven to ten days after fertilization. Fetal stem cells - are taken from the germline tissues that will make up the gonads of aborted fetuses. Umbilical cord stem cells - Umbilical cord blood contains stem cells similar to those found in bone marrow. Placenta derived stem cells - up to ten times as many stem cells can be harvested from a placenta as from cord blood. Adult stem cells - Many adult tissues contain stem cells that can be isolated. 5/4/2018 Dr. Hariom Yadav

Stem Cell Differentiation
5/4/2018 Dr. Hariom Yadav Princeton University

Kinds of Stem Cells Embryonic stem cells come from a five to six-day-old embryo. They have the ability to form virtually any type of cell found in the human body. Embryonic germ cells are derived from the part of a human embryo or foetus that will ultimately produce eggs or sperm (gametes). Adult stem cells are undifferentiated cells found among specialised or differentiated cells in a tissue or organ after birth. Based on current research they appear to have a more restricted ability to produce different cell types and to self-renew. 5/4/2018 Dr. Hariom Yadav

Blastocyst Diagram 5/4/2018 Dr. Hariom Yadav Princeton University

Sexual Reproduction Every cell contains a complete copy of “the blueprint of life” DNA consists of two strands of nucleotides - 4 bases (A,G,T,C) 23 pairs of chromosomes If unwound and tied together, human DNA in one cell would stretch ~ 5 feet, but would be only 50 trillionths of an inch wide! Genes are specific sequences of DNA, each of which “codes” for a protein with a specific function Genes are copied each time a cell divides, passing on the blueprint 5/4/2018 Dr. Hariom Yadav The Association of Reproductive Health Professionals

Stages of Embryogenesis
Day 2 2-cell embryo Day 3-4 Multi-cell embryo Day 1 Fertilized egg Day 5-6 Blastocyst The early stages of embryogenesis are the point at which embryonic stem cell lines are derived. The fertilized egg (day 1) undergoes cell division to form a 2-cell embryo, followed by 4-cell, etc. until a ball of cells is formed by the fourth day. The ball becomes hollow, forming the blastocyst. This is the stage at which pluripotent embryonic stem cell lines are generated. Following the blastocyst stage, the tissues of the embryo start to form and the cells become multipotent. Day 11-14 Tissue Differentiation 5/4/2018 Dr. Hariom Yadav

Derivation and Use of Embryonic Stem Cell Lines
Isolate inner cell mass (destroys embryo) Outer cells (forms placenta) Day 5-6 Blastocyst Inner cells (forms fetus) Culture cells The inner cell mass (the part that would form the fetus) of the embryo is isolated and disrupted to form embryonic cell lines. This process destroys the embryo. Under special culture conditions, the cells of the embryonic lines can be coaxed to form certain kinds of differentiated cell types. In theory, these differentiated cells could be used to repair or replace defective cells or tissues. “Special sauce” (largely unknown) Heart repaired 5/4/2018 Dr. Hariom Yadav Kidney Heart muscle

Embryonic stem cells 5/4/2018 Dr. Hariom Yadav

Adult stem cells 5/4/2018 Dr. Hariom Yadav

Applications Disease Genetic based Disease
Diabetes, Spinal cord injury, Parkinson’s disease, heart disease Genetic based Disease Cystic fibrosis, Huntington’s 5/4/2018 Dr. Hariom Yadav

Unknowns in Stem Cell/Cloning Research
It is uncertain that human embryonic stem cells in vitro can give rise to all the different cell types of the adult body. It is unknown if stem cells cultured in vitro (apart from the embryo) will function as the cells do when they are part of the developing embryo ? Human embryonic stem cells have been studied only recently, so their capabilities are, as of yet, unknown. In theory, the embryonic stem cells are able to form every cell type (which is what they do in the embryo). However, the conditions in culture might not be able to recreate the conditions that give rise to many tissues in the intact embryo. In addition to these unknowns, it is uncertain that the cultured stem cells will function the same as cells that have been developed within the embryo. For example, in a recent study, insulin-producing cells derived from murine embryonic stem cells failed to produce the insulin when transplanted into mice, but only formed tumors.1 In addition, it is uncertain that these lines will continue to proliferate indefinitely without undergoing genetic mutations that render them useless. According to the President's Council on Bioethics: "It is not yet known whether any preparation of human ES cells (generally believed to be much longer-lived than adult stem cells) will continue to grow 'indefinitely,' without undergoing genetic changes."2 References S. Sipione et al Insulin expressing cells from differentiated embryonic stem cells are not beta cells. Diabetologia 47: "Recent Developments in Stem Cell Research." Monitoring Stem Cell Research. The President's Council on Bioethics, January 2004. 5/4/2018 Dr. Hariom Yadav

Challenges to Stem Cell/Cloning Research
Stem cells need to be differentiated to the appropriate cell type(s) before they can be used clinically. Recently, abnormalities in chromosome number and structure were found in three human ESC lines. In order to be used clinically, human embryonic stem cells must be differentiated prior to use in patients. Undifferentiated stem cells could produce tumors and multiply unchecked within a patient, causing more problems than providing appropriate therapy. It is uncertain if conditions can be defined such that all embryonic stem cells differentiate into the correct cell type prior to therapeutic use. Complications caused by undifferentiated cells might not be discovered until years after the first clinical trials are begun. This differentiation problem is acknowledged on the International Society for Stem Cell Research website: "Scientists are still working on developing proper conditions to differentiate embryonic stem cells into specialized cells. As embryonic stem cells grow very fast, scientists must be very careful in fully differentiating them into specialized cells. Otherwise, any remaining embryonic stem cells can grow uncontrolled and form tumors."1 Recently, three established stem cell lines were shown to exhibit abnormalities in chromosome number and structure.2, 3 Obviously, stem cell lines must be checked periodically to make sure the cells do not become abnormal during continued culture. The use of abnormal cells in treatment of patients could result in indeterminate complications. References "Frequently Asked Questions." International Society for Stem Cell Research. Draper, J.S., et al., "Recurrent gain of chromosomes 17q and 12 in cultured human embryonic stem cells," Nature Biotechnology December 7, 2003, advance online publication. C. Cowan et al Derivation of Embryonic Stem-Cell Lines from Human Blastocysts. New England Journal of Medicine 350: 5/4/2018 Dr. Hariom Yadav

Stem cell development or proliferation must be controlled once placed into patients. Possibility of rejection of stem cell transplants as foreign tissues is very high. Undifferentiated stem cells could produce tumors and multiply unchecked within a patient, causing more problems than providing appropriate therapy. According to a recent article ion the New England Journal of Medicine: "There are still many hurdles to clear before embryonic stem cells can be used therapeutically. For example, because undifferentiated embryonic stem cells can form tumors after transplantation in histocompatible animals, it is important to determine an appropriate state of differentiation before transplantation. Differentiation protocols for many cell types have yet to be established. Targeting the differentiated cells to the appropriate organ and the appropriate part of the organ is also a challenge.” Harvard scientists reported in the Proceedings of the National Academy of Sciences that five out of the 19 mice injected with embryonic stem cells developed tumors and died."2 Stem cell lines will suffer the same tissue rejection problems as adult transplants. Once differentiated, these cells will express the HLA tissue antigens programmed by their parental DNA. These antigens must match those of the recipient or else tissue rejection will occur. An admission of the problem of immune rejection can be found from The Scientist: "[W]ithin the [embryonic stem cell] research community, realism has overtaken early euphoria as scientists realize the difficulty of harnessing ESCs safely and effectively for clinical applications. After earlier papers in 2000 and 2001 identified some possibilities, research continued to highlight the tasks that lie ahead in steering cell differentiation and avoiding side effects, such as immune rejection and tumorigenesis.”1 References E. Phimister and J. Drazen Two Fillips for Human Embryonic Stem Cells.” New England Journal of Medicine 350: Bjorklund, L. M., R. Sanchez-Pernaute, et al "Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model." Proceedings of the National Academy of Sciences 99: Hunter, Philip Differentiating Hope from Embryonic Stem Cells. The Scientist 17: 31. 5/4/2018 Dr. Hariom Yadav

Contamination by viruses, bacteria, fungi, and Mycoplasma possible. The use of mouse “feeder” cells to grow ESC could result in problems due to xenotransplantation (complicating FDA requirements for clinical use). Like all immortal cell lines, embryonic stem cell lines must be protected and checked for contamination with viruses, bacteria, fungi, and Mycoplasma. The use of infected lines in patient treatment could have devastating effects. Many embryonic stem cell lines are grown using mouse feeder cells. The mouse cells help the embryonic lines to grow, but pose risks for transplantation due to compatibility problems in human bodies.1 Reference Kennedy, Donald Stem Cells: Still Here, Still Waiting. Science 300: 865. 5/4/2018 Dr. Hariom Yadav

Stem cell and cloning Immune rejection Somatic cell nuclear transfer

Thanks Every cell contains a complete copy of “the blueprint of life” DNA consists of two strands of nucleotides - 4 bases (A,G,T,C) 23 pairs of chromosomes If unwound and tied together, human DNA in one cell would stretch ~ 5 feet, but would be only 50 trillionths of an inch wide! Genes are specific sequences of DNA, each of which “codes” for a protein with a specific function Genes are copied each time a cell divides, passing on the blueprint 5/4/2018 Dr. Hariom Yadav (Time )

INTRODUCTION TO STEM CELL TECHNOLOGY

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