Loss of stem cell regenerative capacity within aged niches

This work uncovers novel mechanisms of aging within stem cell niches that are evolutionarily conserved between mice and humans and affect both embryonic and adult stem cells. Specifically, we have examined the effects of aged muscle and systemic niches on key molecular identifiers of regenerative potential of human embryonic stem cells (hESCs) and post‐natal muscle stem cells (satellite cells). Our results reveal that aged differentiated niches dominantly inhibit the expression of Oct4 in hESCs and Myf‐5 in activated satellite cells, and reduce proliferation and myogenic differentiation of both embryonic and tissue‐specific adult stem cells (ASCs). Therefore, despite their general neoorganogenesis potential, the ability of hESCs, and the more differentiated myogenic ASCs to contribute to tissue repair in the old will be greatly restricted due to the conserved inhibitory influence of aged differentiated niches. Significantly, this work establishes that hESC‐derived factors enhance the regenerative potential of both young and, importantly, aged muscle stem cells in vitro and in vivo; thus, suggesting that the regenerative outcome of stem cell‐based replacement therapies will be determined by a balance between negative influences of aged tissues on transplanted cells and positive effects of embryonic cells on the endogenous regenerative capacity. Comprehensively, this work points toward novel venues for in situ restoration of tissue repair in the old and identifies critical determinants of successful cell‐replacement therapies for aged degenerating organs.

[1]  R. McKay,et al.  Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease , 2002, Nature.

[2]  K. Weber,et al.  Monoclonal antibodies to desmin, the muscle‐specific intermediate filament protein. , 1983, The EMBO journal.

[3]  S. Morrison,et al.  Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing , 2006, Nature.

[4]  J. Faulkner,et al.  Muscle transplantation between young and old rats: age of host determines recovery. , 1989, The American journal of physiology.

[5]  I. Weissman,et al.  Rejuvenation of aged progenitor cells by exposure to a young systemic environment , 2005, Nature.

[6]  T. Partridge,et al.  Muscle satellite cells. , 2003, The international journal of biochemistry & cell biology.

[7]  J. Thomson,et al.  Embryonic stem cell lines derived from human blastocysts. , 1998, Science.

[8]  Leonard I Zon,et al.  The clinical potential of stem cells. , 2004, Current opinion in cell biology.

[9]  T. Holekamp,et al.  Embryonic stem cells differentiate into oligodendrocytes and myelinate in culture and after spinal cord transplantation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[10]  E. Schultz,et al.  Skeletal muscle satellite cells. , 1994, Reviews of physiology, biochemistry and pharmacology.

[11]  Gayle M. Smythe,et al.  Notch-Mediated Restoration of Regenerative Potential to Aged Muscle , 2003, Science.

[12]  F. Dumont.  FK506, an immunosuppressant targeting calcineurin function. , 2000, Current medicinal chemistry.

[13]  D. Fischman,et al.  Monoclonal Antibodies to Desmin: Evidence for Stage‐dependent Intermediate Filament Immunoreactivity during Cardiac and Skeletal Muscle Development a , 1985, Annals of the New York Academy of Sciences.

[14]  J. Mcdonald,et al.  Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord , 1999, Nature Medicine.

[15]  T. Rando,et al.  The regulation of Notch signaling controls satellite cell activation and cell fate determination in postnatal myogenesis. , 2002, Developmental cell.

[16]  M. Kaufman,et al.  Establishment in culture of pluripotential cells from mouse embryos , 1981, Nature.

[17]  M. Sheff,et al.  Age‐related impeded regeneration of mouse minced anterior tibial muscle , 1982, Muscle & nerve.

[18]  Seung K. Kim,et al.  Growth inhibitors promote differentiation of insulin-producing tissue from embryonic stem cells , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[19]  M. Pera,et al.  Characterization and culture of human embryonic stem cells. , 2003, Trends in cardiovascular medicine.

[20]  A. Fassati,et al.  Myogenic cell proliferation and generation of a reversible tumorigenic phenotype are triggered by preirradiation of the recipient site , 2002, The Journal of cell biology.

[21]  E. Ito,et al.  Influences of Immunosuppressive Agents, FK506 and Cyclosporin on Systemic Candida albicans Infection in Mice , 2004, Mycopathologia.

[22]  R. DePinho,et al.  Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a , 2006, Nature.

[23]  H. Schöler,et al.  Formation of Pluripotent Stem Cells in the Mammalian Embryo Depends on the POU Transcription Factor Oct4 , 1998, Cell.

[24]  H. Schöler,et al.  Oct-4: Lessons of Totipotency from Embryonic Stem Cells , 1999, Cells Tissues Organs.

[25]  A. Wagers,et al.  Cellular and Molecular Signatures of Muscle Regeneration: Current Concepts and Controversies in Adult Myogenesis , 2005, Cell.

[26]  A. Petrie,et al.  Stem Cell Function, Self-Renewal, and Behavioral Heterogeneity of Cells from the Adult Muscle Satellite Cell Niche , 2005, Cell.

[27]  K. Ligon,et al.  p16INK4a induces an age-dependent decline in islet regenerative potential , 2006, Nature.

[28]  K. Boheler,et al.  Embryonic stem cells: prospects for developmental biology and cell therapy. , 2005, Physiological reviews.

[29]  Gabriela Kania,et al.  Expression of Pax4 in embryonic stem cells promotes differentiation of nestin-positive progenitor and insulin-producing cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[30]  Thomas A Rando,et al.  Aging, Stem Cells and Tissue Regeneration: Lessons from Muscle , 2005, Cell cycle.