Current Issues in Stem Cell Technologies. Lance D. Trainor, MD OneBlood, Inc.

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1 Current Issues in Stem Cell Technologies Lance D. Trainor, MD OneBlood, Inc.

2 Objective: The big picture of stem cell therapy Outline: Relevant definitions History of Stem Cell Therapy Hematopoietic Stem Cell Transplantation Mesenchymal Stem Cell Transplantation Questions

3 What are stem cells? Undifferentiated cells found throughout the body that 1. Divide to create new stem cells 2. Differentiate into other cell types

4 Differentiation of Stem Cells

5 Stem Cells: 3 Broad Categories Defined by Cell s Ability to Differentiate Totipotent found only in early embryo can create a complete organism, e.g. identical twin Pluripotent exist in undifferentiated inner cell mass of the blastocyst can form any of >200 different cell types found in the body Multipotent derived from fetal tissue, cord blood, and adult tissues ability to differentiate more limited than pluripotent cells

6 Multipotent Stem Cell Stem Cell Hierarchy

7 Stem Cell Timeline

8 Embryonic Stem Cell Research Foundation

9 Adult Stem Cell Research Foundation

10 Multipotent, Adult, stem cells have been isolated from a variety of human tissues

11 Brief History of Stem Cells Early 1900 s: oral administration of bone marrow (BM) to patients with leukemia (unsuccessful) Mid 1900 s: defective BM of mice corrected with intravenous administration of healthy BM 1958: Jean Dausset identified the first of many human histocompatibility antigens (HLA) 1973: first unrelated bone marrow transplant; required 7 transplants for success

12 History (cont.) 1984: Congress passed the National Organ Transplant Act (NOTA) promoted unrelated BM transplantation explored feasibility of establishing a national donor registry 1990: formation of National Marrow Donor Program (NMDP), a non-profit organization that administered the database needed for donors 1990's: rapid expansion and success of bone marrow transplants and programs

13 The Politics of Embryonic Stem Cells 1973: govt. funding moratorium for human embryo research 1988: NIH panel voted 19:2 favoring govt. funding 1990: Congress voted to over-ride moratorium; vetoed by G. Bush B. Clinton lifted ban; but changed his mind the next year 2 o public outcry 1998: DHHS Sec. Sullivan extends moratorium 2000: B. Clinton allows research funding for cells derived from aborted human fetuses, but not embryonic cells

14 US Regulation (ESCs) 2001: G.W. Bush allows funding of research on existing human embryonic stem cell lines 2004: Congress asks G.W. Bush to review his policy on embryonic stem cell research 2004: California Stem Cell Research Funding initiative wins by a 60% to 40% margin Established "California Institute for Regenerative Medicine" to regulate stem cell research and research facilities Issue general obligation bonds to finance institute activities up to $3 billion dollars (annual limit of $350 million)

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16 We are going to discuss clinical uses of two multipotent stem cells

17 1. Hematopoietic Stem Cells multipotent stem cells can differentiate into a variety of blood cells Myeloid Monocytes Macrophages Neutrophils Basophils Eosinophils Megakaryocytes Dendritic Cells Lymphoid T cells B cells NK cells

18 Hematopoietic Stem Cells Platelets RBCs Myeloid Progenitor Neutrophils Macrophages Multipotent Stem Cell Lymphocyte Progenitor B lymphocytes T lymphocytes 23

19 2. Mesenchymal Stem Cells multipotent stem cells derived from mesenchyme (embryonic connective tissue derived from the mesoderm) can differentiate into a variety of cell types (other than hematopoietic cells) osteoblasts chondrocytes myocytes adipocytes as described lately, pancreatic beta cells

20 Mesenchyme meshwork of embryonic connective tissue in the mesoderm that gives rise to the connective tissue of the body &blood vessels

21 Mesenchymal Stem Cells

22 Hematopoietic Stem Cell (HSC) Transplant

23 HSC Transplant HSCs best studied adult stem cells give rise to all blood cells well established clinical use

24 Zhu,Oncogene,2002 Differentiation directed by chemical mediators

25 Disorders treated with HSCs Acute Leukemia Chronic Leukemia Lymphoproliferative Disorders Phagocyte Disorders Inherited Platelet Abnormalities Inherited Metabolic Disorders Histiocytic Disorders Inherited Erythrocyte Abnormalities Inherited Immune System Disorders Plasma Cell Disorders

26 Basic Principle Replenish bone marrow cells eradicated by disease, chemotherapy, or radiation

27 How is it done?

28 Sources of Hematopoietic Stem Cells 1. Bone Marrow 3. Umbilical Cord Blood Stem Cells 2. Peripheral Blood Stem Cells

29 Hematopoietic Stem Cell Transplant 1. Bone marrow stem cells Can be used to replace bone marrow in treatment of leukemias & cancers treated by chemotherapy and/or irradiation, various inherited blood disorders 2. Peripheral blood stem cells (PBSCs) Less invasive than aspirating stem cells from bone marrow (obtained by apheresis collection) 3. Umbilical Cord Blood Stem Cell Transplant Less prone to rejection, decreased incidence of GVHD, and off-the-shelf availability

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35 APHERESIS Carry Away

36 Principles of Apheresis Whole Blood Infusion Red Cell White Cell/Platelets Plasma Filler

37 Apheresis - centrifugal density Component Specific Gravity Plasma Platelets Lymphocytes Granulocytes Red Cells

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39 Separation of Blood Components Mononuclear cells Plasma (lymphocytes, monocytes, PBSCs) Granulocytes Platelets (PMNs, basophils, eosonophils) Red cells

40 Cord Blood Collection

41 Processing Infusion

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43 Mesenchymal Stem Cell (MSC) Transplant

44 Mesenchymal stem cells (MSCs) Progenitors of all connective tissue cells Isolated from bone marrow (BM) and other tissues Grown in culture and differentiated into various tissue-forming cells bone, cartilage, fat, muscle, tendon, liver, kidney, heart, and even brain cells Recent excitement in the practical application of MSCs

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49 Mesenchymal Stem Cell VEGF bfgf PPAR Adipocyte Myo D BMPs Endothelial Cell Skeletal Muscle Osteocyte Chondrocyte 84

50 Tissue Engineering In 1997 Dr Jay Vacanti grew a human ear from cartilage cells the back of a mouse

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52 Examples of Mesenchymal Stem Cell Applications Osteoarthritis of the knee Cardiac muscle regeneration

53 Osteoarthritis Facts Most common form of arthritis Pain, swelling and reduced motion in joints Hands, knees, hips or spine most common Results from break down of cartilage in joints Cartilage: slippery tissue covering the ends of bones in a joint Healthy cartilage absorbs the shock of movement Loss of cartilage results in bones rubbing together Factors that may cause osteoarthritis include Being overweight Getting older Injuring a joint 13.5 million Americans affected 500,000 hospitalizations for osteoarthritis of the knee average charge per hospital stay is greater than $25,000

54 Femur Tibia Fibula

55 Replacement Knee Cartilage Athanasiou and Hu, using donor cells, grew dime-sized disks of cartilage with properties approaching those of native tissue

56 Coronary Heart Disease Facts Caused by atherosclerosis (the narrowing of the coronary arteries due to fatty build up of plaque) Can produce.. angina pectoris (chest pain) heart attack or both Single leading cause of death in America today 1.2 million Americans will have a coronary attack this year 310,000 people a year die of coronary attack in an ER 16,000,000 people alive today have a history of heart attack and/or angina pectoris

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58 Stem Cell Candidates for Myocardial Transplantation

59 Stem cells transplanted to teen's heart Experimental procedure aims to grow new muscle, vessels Thursday, March 6, 2003 Posted: 11:50 AM EST (1650 GMT) Stem cells transplanted to teen's heart Experimental procedure aims to grow new muscle, vessels Thursday, March 6, 2003 Posted: 11:50 AM EST (1650 GMT) ROYAL OAK, Michigan (AP) -- Doctors said Wednesday they are attempting an experimental procedure to heal a teenage patient's heart by infusing it with the boy's own blood stem cells. It could take months to know whether it works, but doctors say they are already seeing encouraging results.

60 Other Applications for Mesenchymal Stem Cells in Study

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