Year 4

Although functional organ stem cells persist in the old, tissue damage invariably overwhelms tissue repair, ultimately causing the demise of an organism. The poor performance of stem cells in an aged organ, such as skeletal muscle, is caused by the changes in regulatory pathways such as Notch, MAPK and TGF‐β, where old differentiated tissues and blood circulation inhibit the regenerative performance of organ stem cells. While responses of adult stem cells are regulated extrinsically and age‐specifically,
our work recently published puts forward experimental evidence suggesting that embryonic cells have an intrinsic youthful barrier to aging and produce soluble pro‐regenerative proteins that signal the MAPK pathway for rejuvenating myogenesis. Future identification of this activity will improve our understanding of embryonic versus adult regulation of tissue regeneration suggesting novel strategies for organ rejuvenation. Comprehensively, our progress of the last year indicates that if the age‐imposed decline in the regenerative capacity of stem cells was understood, the debilitating lack of organ maintenance in the old could be ameliorated and perhaps, even reversed.The same understanding is also required for successful transplantation of stem and progenitor cells into older individuals and for combatting many tissue degenerative disorders: namely, productive performance of transplanted cells is dependent on the niche into which they are placed and the inhibitory factors of the aged and pathological niches need to be identified and neutralized. Additional recently published work was focused on developing new strategies for providing new source of regenerative cells to people who suffer from genetic myopaties (where their own muscle stem cells become exhausted due to the progression of the disease). Muscle regeneration declines with aging and myopathies, and reprogramming of differentiated muscle cells to their progenitors can serve as a robust source of therapeutic cells. We utilized small molecule inhibitors to dedifferentiate muscle into dividing myogenic cells, without gene over expression, which is clinically adaptable. The reprogrammed muscle precursor cells contributed to muscle regeneration in vitro and in vivo and were unequivocally distinguished because of the lineage marking method. These findings enhance understanding of cell-fate determination and create novel therapeutic approaches for improved muscle repair. Moreover, one more of our recently published papers has identified new ways of making muscle progenitor cells to fuse more robustly into muscle fibers, hence enabling deliberate control of muscle tissue formation. We are at the latest stages in our work on the design of novel biomimetic stem cell niches, which based on our current results make easy to expand in culture progenitor cells (e.g. derived from paints) akin to muscle stem cells and enhancing the efficiency of cell transplantation to such an extent that progressive muscle loss in genetic myopathies is predicted to be averted. We have also deciphered some of the fundamental properties of embryonic stem cells, which would enable deliberate control of their self-renewal and tissue specific differentiation and the manuscript describing these findings has been submitted to Cell.