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Stem Cells and the Cardiovascular System

Explore the role of stem cells in the cardiovascular system, including their different types, functions, and potential applications.

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Stem Cells and the Cardiovascular System

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  1. Stem Cells and the Cardiovascular System 20 October 2011 Robert Siggins, Ph.D. stemcellschool.com

  2. Outline and Objectives • What are stem cells (SCs)? • Which SCs contribute to the adult CV system? • What are the physiological and pathophysiological roles for SCs in the CV system?

  3. Stem Cell “Theory” • 1855  First eluded to by (Remak) Virchow  Omnis cellula e cellula • RediOmne vivum ex ovo • 1875  ”Embryonic rest” proposed by Cohnheim (cancer stem cells) • 1917  HSC proposed by Pappenheim • 1961  McCulloch and Till describe CFU-s

  4. Definition of SCs • Totipotent, pluripotent, or multipotent • Self-renewal • Clonogenic • Niche http://icanhascheezburger.com

  5. Totipotent = ability to give rise to all cells of the body and all cells that constitute the extraembryonic tissues (i.e. placenta) Self-renewal Pluripotent = ability to make all cells of the body (all three germ layers) Multipotent = ability to differentiate into more than one cell type (usually germ layer restricted) autismpedia.org

  6. Embryonic SCs (ESCs) are pluripotent Tissue-restricted SCs are Multipotent! stemcellresources.org

  7. stemcellresources.org

  8. toonpool.com

  9. UEA-1 (ulexeuropaeus agglutinin-1) or SSEA-4 (stage-specific embryonic antigen-4) eliminates teratoma-initiating cells! Physiol Rev 85:1373-1416, 2005

  10. Definition of SCs • Totipotent, pluripotent, or multipotent • Self-renewal • Clonogenic • Niche

  11. Symmetric and Asymmetric Divisions http://xarquon.jcu.cz/edu/hematologie/03kmenove_bunky/03stem_lineages.htm

  12. Cell Extrinsic and Intrinsic Models Regulated by niche attachment Regulated by niche cell polarity Regulated by intrinsic polarity

  13. Asymmetric Divvision

  14. Definition of SCs • Totipotent, pluripotent, or multipotent • Self-renewal • Clonogenic • Niche

  15. Cardiac Stem Cells (CSCs) Large clone of c-kit+ cells (green) generated by a single rat c-kit+ CSC. Physiol Rev 85:1373-1416, 2005

  16. Cardiac Stem Cells (CSCs) Clonogenic cells in differentiating medium acquire the myocyte phenotype (α-sarcomeric actin, red). Physiol Rev 85:1373-1416, 2005

  17. Cardiac Stem Cells (CSCs) Clonogenic cells acquire the SMC phenotype (α-smooth muscle actin, magenta). Physiol Rev 85:1373-1416, 2005

  18. Cardiac Stem Cells (CSCs) Clonogenic cells acquire the EC phenotype (vWF, yellow). Physiol Rev 85:1373-1416, 2005

  19. Definition of SCs • Totipotent, pluripotent, or multipotent • Self-renewal • Clonogenic • Niche

  20. Niches are specialized microenvironmnets comprising support cells, soluble factors, ECM, SCs, and progenitor cells Every niche is unique!

  21. http://stemcells.nih.gov/info/

  22. Cardiac niches and putative supporting cells. Apical (A, B, and F) and atrial (C–E) niches contain CSCs and LCCs. (A) c-kit+ (green) Ets1+ (white; EC progenitors). (B) MDR1+ cells (white) GATA-4+ (magenta dots); α-sarcomeric actin+GATA-4+ (red; myocyte precursors). GATA-4+ cardiac progenitors (arrowheads). (C) Sca-1+MEF2C+ (yellow & white dots; myocyte progenitors); Sca-1+von Willebrand factor+ (green; EC precursor). (D–F) Connexin 43 and E- and N-cadherin in niches containing c-kit+ (D & F, green) and Sca-1+ (E, yellow) CSCs and LCCs. GATA-4+ (D, magenta dots) and MEF2C+ (E & F, yellow dots). Connexin 43 (yellow dots), E-cadherin (green dots), and N-cadherin (white dots) Nuclei are stained by propidium iodide (blue). PNAS 103:9226-9231, 2006

  23. Cardiac niches and putative supporting cells. (G–J) Connexin 43 and 45 and N- and E-cadherin in atrial niches containing c-kit CSCs–LCCs (green) are represented by yellow dots located between two CSCs–LCCs (arrowheads), a CSC–LCC and a fibroblast (arrows), and a CSC–LCC and a myocyte (double arrowheads); see Insets. Nuclei are stained by propidium iodide (blue). PNAS 103:9226-9231, 2006

  24. Formation of Gap Junctions PNAS 103:9226-9231, 2006

  25. PNAS 103:9226-9231, 2006 Myocyte turnover and life span (A and B) Apical section illustrating bright (arrows), intermediate (open arrowheads), and dim (arrowheads) BrdU+ myocyte nuclei (yellow) after 10 weeks of chasing. Myocytes are stained by cardiac myosin (B, red).

  26. Myocyte Turnover (C) % of BrdU-bright, -int, and -dim myocyte nuclei. (Right) Bars document the total number of BrdU+ myocytes and total number of myocytes in the atria, base–mid region, and apex. PNAS 103:9226-9231, 2006

  27. Myocyte Turnover PNAS 103:9226-9231, 2006

  28. Myocyte Turnover PNAS 103:9226-9231, 2006

  29. Myocyte Lifespan PNAS 103:9226-9231, 2006

  30. ESCs versus Adult SCs (ASCs) • ESCs • Embryolically derived • Not tissue-specific • Pluripotent • Requires in vitro fertilized egg for derivation (ethical concerns) • ASCs • Tissue resident • Tissue-specific • Multipotent • No ethical problems with their clinical application

  31. nature.com

  32. americanprogress.org

  33. http://stemcells.nih.gov/info/media/

  34. Outline and Objectives • What are stem cells (SCs)? • Which SCs contribute to the adult CV system? • What are the physiological and pathophysiological roles for SCs in the CV system?

  35. A B C D Identification of Mitotic Spindles in Dividing Myocytes from Infarcted Hearts (A) blue = organization of tubulin in the mitotic spindle (arrows) (B) green = metaphase (arrowheads) (C) green and blue = combination of tubulin and metaphase chromosomes (arrows and arrowheads) (D) red = sarcomeric α-actin, blue = tubulin, and green = chromosomes in metaphase (arrows and arrowheads) N Engl J Med 344:1750-1757, 2001

  36. A Myocyte in the Process of Cytokinesis Arrows = actin Red = staining of myocyte sarcomeric α-actin green = PI labeling of chromosomes N Engl J Med 344:1750-1757, 2001

  37. Effects of MI on the Number of Mitotic Myocytes N Engl J Med 344:1750-1757, 2001

  38. The Y Chromosome in Transplanted Hearts. • Myocytes (A and B) • Smooth-muscle cells (C and D), Endothelial cells in both coronary arterioles (E and F), and capillary endothelial cells (G and H) • Blue areas = PI staining in nuclei, Green areas indicate Y chromosome • The red areas indicate sarcomeric α-actin in B, of smooth-muscle α-actin in D, and of factor VIII in F and H. N Engl J Med 346:5-15, 2002

  39. The Y Chromosome in Transplanted Hearts. In I, J, and K, the bright blue, fluorescent areas and the arrows indicate the presence of Ki-67, and the yellow areas show the Y chromosomes. N Engl J Med 346:5-15, 2002

  40. ASCs of the CV system • Isolated based on functional assessments or surface phenotypes • Cardiac Stem Cells (CSCs) and Endothelial Progenitor Cells (EPCs) • Possible Vascular Progenitor Cell (VPC); resident in vessel walls

  41. Surface Markers for EPCs • Mouse • VEGFR2, LinNeg, c-kit, Sca-1, VE-cadherin • Human • CD133, VEGFR2, VE-cadherin, CD34

  42. Cell 127:1137-1150, 2006

  43. Vasculogenesis • Aggregation of de-novo-forming angioblasts into a primitive vascular plexus • Hemangioblast Flk1+ cells produce ECs and hematopoietic cells • Earliest marker of angioblast precursors  Flk1/VEGFR-2 • Complex remodeling processgrowth, migration, sprouting and pruning lead to development of functional circulatory system

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