1,Stem Cell : Physiology roundness Biochemic character: higher activity of telomerase Characters of proliferation: slowness & self-steady,47,Stem cell plasticity,The ability of stem cells from one adult tissue to generate the cell types of another tissue. These stem cells have “transdifferentiating”potential. The ability of adult stem cells to exhibit plasticity increases their therapeutic potential considerably Wagers and Weissman 2004 Cell 116:639-648.,48,49,Transdifferentiation,The conversion of one differentiated cell type to another. Criteria: The differentiated states before and after the conversion must be clearly defined. Require both biochemical and morphological characterization. The cell lineage relationship between the two cell types needs to be clearly established. Require lineage labeling,50,Adult Stem Cell Transdifferentiation,Over the past 5 years: BMT (bone marrow transplants) Donor cells differentiated into muscle cells. Cells derived from brain and muscle Hematopoietic reconstitution of lethally irradiated mice,51,52,Hematopoietic Nonhematopoietic Are all conversions due to HSC Plasticity? It is particularly difficult to verify true conversion of nonhematopoietic to hematopoietic: HSCs could be contaminants reaching via circulation: Proved to be true,53,Demonstration of BM PlasticityBone Marrow to Liver,Male to female BMT in Rats, Mice and Human Hemopoietic reconstitution + Liver cells of donor origin Two requirements: Liver damage Inability of endogenous repair,54,Bone Marrow to Liver,FAH: Mice deficient in fumarylacetoacetate hydrolase leading to progressive liver and kidney failure due to tyrosinemia unless they are treated with NTBC to prevent the breakdown of tyrosine into toxic metabolites. lacZ mouse: labeled with -galactosidase.,55,Bone Marrow to Heart/CardiacMuscles: Experimental,Study 1: Mice with experimentally induced myocardial infarction Intracardiac injection of whole marrow (or Kit+ BM cells) during the initial post infarct period: Improve the outcome by: 1. BM cells endothelial cells increased vascularity 2. BMSC Cardiac myocytes 3. Production of cytokines and other factors promote myogenic outcome repair and prevent fibrosis,56,Study 2: SCF & G-CSF (40 fold in circulating BMSC pool) administered during the peri-infarct period Improve cardiac outcome post-infarct THOUGH: these growth factors may exert ameliorative effects unrelated to stem cells. YET: It is, any way, clinically beneficial,57,Bone Marrow to Heart/CardiacMuscles: In Human,Two phase In studies: 1. Intracardiac injection of autologous BM cells post- infarct: Safe, improved cardiac function 2. AC133+ BM cells injected into infarct borders following coronary artery bypass grafting: improved perfusion and cardiac function,58,Caution: 1. Small number of patients. 2. No controls 3. BM to myocyte differentiation cannot be traced in the autologous setting. Hope: Studies to assess whether BM administration or mobilization would help in the treatment of ischaemic heart disease are going on.,59,60,Why is Stem Cell Research So Important to All of Us?,Stem cells allow us to study how organisms grow and develop over time. Stem cells can replace diseased or damaged cells that can not heal or renew themselves. We can test different substances (drugs and chemicals) on stem cells. We can get a better understanding of our “genetic machinery.”,61,What Human Diseases are Currently Being Treated with Stem Cells?,Parkinsons Disease Leukemia (Bone Marrow Transplants) Skin Grafts resulting from severe burns Stem Cell Therapy has the Potential to: Regenerate tissues/organs Cure diseases like diabetes, multiple sclerosis, etc.,62,What are the key questions about ASC?,How many kinds of ASC exist, and in which tissues do they exist? What are the sources of ASC in the body? Are they leftover embryonic stem cells, or do they arise in some other way? Why do they remain in an undifferentiated state when all the cells around them have differentiated? Do ASC normally exhibit plasticity, or do they only transdifferentiate when scientists manipulate them experimentally? What are the signals that regulate the proliferation and differentiation of stem cells that demonstrate plasticity? Is it possible to manipulate ASC to enhance their proliferation so that sufficient tissue for transplants can be produced? Does a single type of stem cell existpossibly in the bone marrow or circulating in the bloodthat can generate the cells of any organ or tissue? What are the factors that stimulate stem cells to relocate to sites of injury or damage? ,63,On March 9, 2009, President Barack Obama issued Executive Order (EO) 13505, entitled : Removing Barriers to Responsible Scientific Research Involving Human Stem Cells,64,