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Asymmetric Self-Renewal By Distributed Stem Cells:

Asymmetric Self-Renewal By Distributed Stem Cells: Misunderstood in the Past, Important for the Future James L. Sherley, M.D., Ph.D. Director The Adult Stem Cell Technology Center, LLC Boston, MA, USA. ASCTC. Post-Embryonic. Fetal SCs Germline SCs Post-natal SCs Somatic SCs Tissue SCs

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Asymmetric Self-Renewal By Distributed Stem Cells:

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  1. Asymmetric Self-Renewal By Distributed Stem Cells: Misunderstood in the Past, Important for the Future James L. Sherley, M.D., Ph.D. Director The Adult Stem Cell Technology Center, LLC Boston, MA, USA ASCTC

  2. Post-Embryonic Fetal SCs Germline SCs Post-natal SCs Somatic SCs Tissue SCs Adult SCs Epiblasts [embryonic SCs] Embryonic precursors Distributed Stem Cells? (DSCs) Sources of Stem Cells (SCs) During Mammalian Development ASCTC Fetal, Neonatal, Adult Development Early Embryonic Development Embryonic

  3. “DISTRIBUTED STEM CELLS” DSCs (Sherley, 2008, Breast Disease29, 37-46) For Distributed Potency Asymmetric Self-Renewal In vivo and in vitro Post-Embryonic Fetal SCs Germline SCs Post-natal SCs Somatic SCs Tissue SCs Adult SCs ASCTC Embryonic stem cells Primordial germ cells Induced pluripotent SCs Symmetric Self-Renewal In vitro Embryonic

  4. The Pervasive Stem Cell Definition: Self-renewal or Differentiation ASCTC Symmetric Self-renewal

  5. An Inadequate Definition For Distributed Stem Cells The Pervasive Stem Cell Definition: Self-renewal or Differentiation ASCTC Symmetric Self-renewal

  6. A Gnomonic for Distributed Stem Cells: Self-renewal AND Differentiation, continuously and simultaneously ASCTC “Asymmetric Self-renewal”

  7. Potten et al., 2003 Tissue Cell Turnover The mark of distributed stem cells (DSCs): Asymmetric Self-Renewal • Death • Terminal • Arrest • Differentiation • Symmetric • Kinetics • Asymmetric • Self-renewal • Cell Kinetics ASCTC DSC (niche)

  8. A CENTRAL QUESTION: What is the cell kinetics form of asymmetric self-renewal? ASCTC

  9. 1-p p Mathematical Identity, but vs. ASCTC Stochastic Determined Biological Distinctions

  10. 1-p p Biological Distinctions vs. ASCTC Stochastic Extinction probability Mutation accrual Determined No DSC differentiation Individual asymmetric division Mutation avoidance? Unique cellular programs!

  11. Developmental Asymmetric Divisions Are Not Equivalent to Asymmetric Self-Renewal Divisions ≠ ASCTC • Asymmetric Division • Sisters unequal • Both sisters differ from parent • Limited • Asymmetric Self-Renewal • Sisters unequal • One sister equal to parent • Continuous over lifespan

  12. 1-p p Biological Distinctions vs. ASCTC Stochastic Extinction probability Mutation accrual Determined No DSC differentiation Individual asymmetric division Mutation avoidance? Unique cellular programs!

  13. Asymmetric Self-Renewal Associated (ASRA) Genes: Highly Specific Biomarkers for DSCs + SYM ASYM DNA ASCTC CyA SYM CXCR6 ASYM Phase [Noh et al. 2011, PLoS ONE] [Taghizadeh et al., 2010, PLoS ONE]

  14. Proposed Stem Cells for Tissue Replacement Stem Cell Therapy ASCTC “Adult” Stem Cells (DSCs) Embryonic Stem Cells (ESCs) Induced Pluripotent Stem Cells (iPSCs)

  15. Mathematical Features of Cell Production with Differentiation p 1-p Embryonic and iP Stem Cells b Loss of Stemness a c a (In Vitro) Self-Renewal OR Differentiation a d ASCTC Stemness Preserved “Asymmetric Self-Renewal” Distributed Stem Cells Stochastic Deterministic Self-Renewal AND Differentiation

  16. Proposed Stem Cells for Tissue Replacement Stem Cell Therapy ASCTC “Adult” Stem Cells (DSCs) Embryonic Stem Cells (ESCs) Induced Pluripotent Stem Cells (iPSCs)

  17. Tissue Therapy with ESCs and iPSCs? Damaged or Diseased Tissue Normal Tissue REPAIR? ASCTC

  18. Tissue Therapy with ESCs and iPSCs Damaged or Diseased Tissue Normal Tissue Short-lived Repair!!!! ASCTC (Tumors!) hESCs and iPSCs - ethical issues (hESCs) - epigenetic defects - genetic defects Purification - ESCs! - iPSCs! - other differentiated cells “Develop In Vitro” Differentiated Cells (Immature)

  19. Tissue Therapy with Distributed Stem Cells Renewing Repaired Tissue Damaged or Diseased Tissue Normal Tissue ASCTC • Autologous • Allogeneic • Informed Consent - purity not required - expansion not always critical DSC Expansion is possible!

  20. An DSC Bottleneck for Tissue Therapy Damaged or Diseased Tissue Normal Tissue Repaired Tissue? ASCTC Tumor Risk Remains hESCs and iPSCs - ethical issues (hESCs) - epigenetic defects - genetic defects “Develop In Vitro” Isolate, stabilize, expand Distributed Stem Cells Differentiated Cells (Immature) [Sherley, J. L. 2004, J. Biomed. Biotech. 2, 71-72.]

  21. Distributed Stem Cell Asymmetric Self-Renewal ASCTC Immature? Embryonic development iPSCs hESCs ?

  22. Distributed Stem Cell Asymmetric Self-Renewal ASCTC Immature? Embryonic development iPSCs hESCs ? Xanthine (p53-KO mimic) Disease Research Pare & Sherley, 2011, J. Biomed. Biotech. New Patent: USPTO No. 8,759,098, June 24, 2014

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