Stem Cells And Potential Clinical Applications

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Stem Cells And Potential Clinical Applications

  1. 1. Stem cells and potential clinical applications รศ . อาทิตย์ อังกานนท์ ภาควิชาอายุรศาสตร์ คณะแพทยศาสตร์โรงพยาบาลรามาธิบดี มหาวิทยาลัยมหิดล
  2. 2. Embryo development http :// www . youtube . com / watch?v = mUcE1Y_bOQE
  3. 3. Capabilities of stem cell <ul><li>Self renewal </li></ul><ul><li>Pluripotency </li></ul>
  4. 4. Promise of stem cells research Regenerative Medicine . Department of Health and Human Services. August 2006.
  5. 5. Stem cell heirachy One kind of tissue Monopotent stem cells Tissues in same germ layer Multipotent stem cells Embryo Pleuripotent stem cells Embryo and placenta Totipotent stem cells Capability of development Type of stem cells
  6. 6. Sources of stem cells <ul><li>Embryonic stem cells </li></ul><ul><ul><li>Difficult to harvest and culture </li></ul></ul><ul><li>Adult stem cells </li></ul><ul><ul><li>Adult stem cells in tissue </li></ul></ul><ul><ul><li>iPS (induced pluripotent stem cells) adult cells reprogrammed </li></ul></ul>
  7. 7. Reprogramming Scientific Breakthrough of the Year 2008 (Science Magazine) Mature, specialized adult cells Induced Pleuripotent Stem Cells (ES cells liked) Four genes inserted Patient specific cells <ul><li>Neurons from ALS </li></ul><ul><li>Myocytes from Muscular Dystrophy Beta cells from Type I DM </li></ul>Another type of specialized cells Pancreatic exocrine cells to beta cells
  8. 8. Do stem cells exist in adult? <ul><li>Yes. </li></ul><ul><ul><li>Hematopoietic system </li></ul></ul><ul><ul><li>Skin and integument system </li></ul></ul><ul><ul><li>Epithelium system </li></ul></ul><ul><li>Probably. </li></ul><ul><ul><li>Neurons </li></ul></ul><ul><ul><li>Cardiomyocytes </li></ul></ul>
  9. 9. Why bone marrow? http :// stemcells . nih . gov / info / scireport / chapter5 . asp
  10. 10. Stem cell enrichment <ul><li>Cultivation and expansion </li></ul><ul><li>Selection </li></ul>
  11. 11. Potentials <ul><li>Hematologic diseases </li></ul><ul><li>Cardiovascular diseases </li></ul><ul><li>Neurologic diseases </li></ul><ul><li>Diabetes </li></ul><ul><li>All degenerative conditions </li></ul>
  12. 12. Hematopoietic stem cell transplantation <ul><li>Established procedure </li></ul><ul><li>Allogeneic stem cell transplantation </li></ul><ul><li>Autologous stem cell transplantation </li></ul>
  13. 13. Concept <ul><li>Replacement of diseased marrow with new, healthy one. = Allogeneic </li></ul><ul><ul><li>Malignant disease </li></ul></ul><ul><ul><li>Marrow failure </li></ul></ul><ul><ul><li>Congenital disease </li></ul></ul><ul><li>Supportive measure after high dose chemotherapy (with cryopreserved stem cell) = Autologous </li></ul><ul><ul><li>Malignant disease with clean marrow </li></ul></ul><ul><ul><li>Autoimmune disease </li></ul></ul>
  14. 14. Allogeneic transplantation <ul><li>Needs healthy marrow </li></ul><ul><ul><li>allogeneic </li></ul></ul><ul><ul><li>syngeneic </li></ul></ul><ul><li>Donor must be HLA compatible </li></ul>
  15. 15. HLA system <ul><li>Class I </li></ul><ul><ul><li>A </li></ul></ul><ul><ul><li>B </li></ul></ul><ul><ul><li>C </li></ul></ul><ul><li>Class II : DR, DQ, DW </li></ul><ul><li>Each has more than 50 pleomorphisms </li></ul><ul><li>Both are on chromosome 6 </li></ul>
  16. 16. HLA system inheritance พ่อ แม่
  17. 17. HLA compatibility ผู้ป่วย HLA identical Haploidentical Unidentical
  18. 18. Donor อื่น นอกเหนือจากพี่น้อง <ul><li>Matched unrelated donor </li></ul><ul><li>Must be HLA identical of both Class I and II </li></ul><ul><li>Chance to find is 1:100,000 to 1:1,000,000 in normal, same ethnic population </li></ul><ul><li>Need donor registry system such as in US, Europe, Japan </li></ul>
  19. 19. การใช้ BMT เป็น supportive measure <ul><li>Autologous BMT </li></ul><ul><li>มีการเก็บ stem cell ของผู้ป่วยมาเก็บไว้ก่อน โดย cryopreservation ที่ -80 o C หรือ liquid nitrogen </li></ul><ul><li>หลังจากเก็บ stem cell ผู้ป่วยจึงจะได้รับ high dose chemotherapy ในขนาด myelo-ablative หรือ sub-ablative </li></ul><ul><li>หลังจาก high dose chemotherapy เสร็จสิ้น จึงจะให้ stem cell ที่เก็บไว้คืนเข้าไป </li></ul>
  20. 20. Procedure <ul><li>Donor identification </li></ul><ul><li>Stem cell collection </li></ul><ul><li>Pretransplant preparation </li></ul><ul><ul><li>Conditioning regimen </li></ul></ul><ul><ul><li>Immunosuppression </li></ul></ul><ul><li>Transplantation </li></ul><ul><li>Post transplantation </li></ul><ul><ul><li>Supportive measure </li></ul></ul><ul><ul><li>Immunosuppression </li></ul></ul>
  21. 21. Stem cell collection <ul><li>Source of stem cell </li></ul><ul><li>Bone marrow </li></ul><ul><ul><li>มี stem cell อยู่ประมาณ 1% ตลอดเวลา </li></ul></ul><ul><li>Peripheral blood </li></ul><ul><ul><li>ต้องกระตุ้นให้ stem cell ออกมา จึงจะเก็บได้ </li></ul></ul><ul><ul><li>ระยะเวลาฟื้นตัวหลัง transplant สั้นกว่าใช้ stem cell จาก bone marrow </li></ul></ul>
  22. 22. Indications of HSCT <ul><li>Aplastic anemia </li></ul><ul><li>Malignant diseases </li></ul><ul><li>Genetic diseases </li></ul><ul><li>Immunologic diseases </li></ul><ul><li>Solid organ transplantation </li></ul>
  23. 23. Immunosuppression <ul><li>ใช้ในกรณีทำ allogeneic bone marrow transplantation </li></ul><ul><li>ยาที่ใช้ : Cyclosporin A, Methotrexate โดยเริ่มให้ตั้งแต่ 1 วันก่อนทำ transplant </li></ul><ul><li>จุดประสงค์ในการให้ เพื่อกด immune response ของ graft ที่ไปพร้อมกับ T cells ไม่ให้ทำอันตรายกับ host (graft versus host disease) </li></ul><ul><li>หยุดได้ 6 เดือนหลังทำ transplant </li></ul>
  24. 24. Post transplantation <ul><li>ภาวะแทรกซ้อนที่สำคัญ </li></ul><ul><li>อันตรายจาก pancytopenia เหมือนคนไข้ได้ chemo ทั่วไป </li></ul><ul><li>อันตรายจาก conditioning regimen </li></ul><ul><li>อันตรายจาก graft (graft versus host disease : GVHD) </li></ul><ul><li>Graft failure </li></ul>
  25. 25. Graft versus host disease <ul><li>เป็นปฏิกิริยาต่อต้านเนื้อเยื่อ (rejection) ที่ T cell ใน graft กระทำต่อ host </li></ul><ul><li>เกิดเมื่อมี graft T cell สามารถ survive ได้ใน host และ host ไม่สามารถกำจัดได้ </li></ul><ul><li>ถ้าเกิดใน 100 วันแรก = acute GVHD </li></ul><ul><li>ถ้าเกิดหลัง 100 วัน = chronic GVHD </li></ul>
  26. 26. Chimerism – the beauty of HSCT <ul><li>Co-existence of stem cells from two organisms </li></ul><ul><li>Co-existence of immunologic effector cellss from two organisms </li></ul><ul><li>Chimerism can lead to immune tolerance </li></ul>
  27. 27. The Graft-versus-”Disease” Effect <ul><li>HSCT also includes transplantation of donor T cells </li></ul><ul><li>These T cells, if not well controlled, can lead to fatal Graft versus Host disease (GVHD) </li></ul><ul><li>Can we ‘selectively’ direct these T cells against just disease, not normal tissue? </li></ul>
  28. 28. HSCT offers beyond the effects of chemotherapy <ul><li>Allogeneic transplantation is more successful in aplastic anemia than syngeneic transplantation </li></ul><ul><li>Donor lymphocyte infusion can bring leukemia relapse into remission </li></ul><ul><li>Immune tolerance could be useful in solid organ transplantation </li></ul>
  29. 29. Potential in CardioVascular Diseases <ul><li>Angiogenesis for coronary vascular diseases </li></ul><ul><li>Myocardial regeneration for cardiomyopathy </li></ul>
  30. 30. Potential sources of stem cells used for heart diseases <ul><li>Embryonic stem cells </li></ul><ul><li>Skeletal myoblasts </li></ul><ul><li>Human adult bone-marrow derived cells </li></ul><ul><li>Mesenchymal (bone marrow stromal) cells </li></ul><ul><li>Resident cardiac stem cells </li></ul><ul><li>Endothelial progenitor cells </li></ul><ul><li>Peripheral blood CD34+ cells </li></ul>
  31. 32. Lunde, et al (Norway) <ul><li>Anterior wall MI with 3 or more hypokinetic LV segments </li></ul><ul><li>Intracoronary infusion of BM derived MNC after stenting in anterior wall MI within 6 days </li></ul><ul><li>RCT, about 50 pts in each arm </li></ul><ul><li>Cells used : BM MNC (separated by Ficolling) </li></ul><ul><li>No improvement of LV function compared to control </li></ul>
  32. 33. Assmus, et al (Frankfurt Germany) <ul><li>Patients with LV dysfunction following MI (within 3 mo.) </li></ul><ul><li>N (total) = 71, randomized to 3 groups : no cells, PB MNC, BM MNC </li></ul><ul><li>Cells prepared by Ficolling </li></ul><ul><li>Improved global LVEF, regional wall motion, and reduced end systolic volume in group that received BM MNC </li></ul>
  33. 34. Schachinger, et al (Frankfurt Germany) <ul><li>Pts with acute STEMI, reperfused, and have LVEF<45% </li></ul><ul><li>Cells used : BM MNC (Ficolling) </li></ul><ul><li>RCT with placebo: about 100 in each group </li></ul><ul><li>Improved LVEF, especially in group that have low baseline LVEF and have infusion more than 4 days after reperfusion </li></ul>
  34. 35. Other approach <ul><li>Use G-CSF after MI to increase circulating stem cells FIRSTLINE-AMI STEMMI REVIVAL-2 </li></ul><ul><li>Mixed results </li></ul>
  35. 36. Unanswered questions <ul><li>Timing </li></ul><ul><li>What kind of cells? </li></ul><ul><li>Method of delivery </li></ul>There is definitely a role of stem cells in cardiac repair.
  36. 37. Stem cells and nervous system <ul><li>Adult neural stem cells exist in the CNS </li></ul><ul><li>These slow dividing cells give rise to neuron and glia cells </li></ul><ul><li>ES can be induced to differentiate into neuron </li></ul><ul><li>Growth & trophic factors for nervous system have been identified </li></ul>
  37. 38. Potential in Neurologic diseases <ul><li>Parkinson’s disease </li></ul><ul><li>Stroke </li></ul><ul><li>Neuron loss </li></ul><ul><ul><li>ALS </li></ul></ul><ul><ul><li>Injuries </li></ul></ul>
  38. 39. Parkinson’s disease <ul><li>Neuron loss in substantia nigra </li></ul><ul><li>RCT using cultured mesencephalic tissue from four embryos was implanted into the putamen of severe Parkinson’s patients </li></ul><ul><li>Treatment did not improve movement disorders, but transplanted neuron can survive in patients’ brain </li></ul>
  39. 40. Parkinson’s Disease <ul><li>Researches focus on using more primitive ES cells </li></ul><ul><li>ES cells can be induced into dopamine neurons that survive longer in the patients </li></ul><ul><li>Nuclear transfer into these cells can provide genetic match </li></ul><ul><li>Triggers for brain auto-repair are currently investigated </li></ul>
  40. 41. Other neuron loss: challenging issues <ul><li>Oligodendrocytes development from ES </li></ul><ul><li>Axon growth and connections </li></ul>
  41. 42. Peripheral vascular diseases <ul><li>Cells used </li></ul><ul><ul><li>BM MNC </li></ul></ul><ul><ul><li>Mobilized PBSC </li></ul></ul><ul><li>Methods of delivery </li></ul><ul><ul><li>Intramuscular injection in the affected limb </li></ul></ul>Huang PP, et al . Thromb Haemost . 2007;98 ( 6 ): 1335-42 .
  42. 43. Diabetes <ul><li>The use of stem cells </li></ul><ul><li>Identify beta-cell precursor </li></ul><ul><li>Stem cells could be induced to differentiate into beta-cell ex-vivo or in-vivo </li></ul><ul><li>Search for adult pancreatic stem cells in pancreas </li></ul>Edmonton protocol
  43. 44. Facial contour defects <ul><li>Dermal filler </li></ul><ul><li>Post auricular punch biopsy – propietary culture system – intralesion injection </li></ul>Weiss RA, et al . Dermatol Surg . 2007;33 ( 3 ): 263-8 .
  44. 45. Further readings <ul><li>NIH Stem Cells Information http :// stemcells . nih . gov / </li></ul>

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