(558c) Stem Cell Senescence: Nanog Reverses the Effects of Organismal Aging On Proliferation and Myogenic Differentiation Potential of Mesenchymal Stem Cells

Although the therapeutic potential of mesenchymal stem cells (MSC) is widely accepted, loss of cell function due to donor aging or culture senescence are major limiting factors hampering their clinical application. Our laboratory recently showed that MSC originating from older donors suffer from limited proliferative capacity and significantly reduced myogenic differentiation potential. This is a major concern, as the patients most likely to suffer from cardiovascular disease are elderly. Here we tested the hypothesis that a single pluripotency associated transcription factor, namely Nanog, may reverse the proliferation and differentiation potential of BM-MSC from adult donors. Our microarray analysis showed that adult (a)BM-MSC expressing Nanog clustered close to Nanog-expressing neonatal cells. Nanog markedly upregulated genes involved in cell cycle, DNA replication and DNA damage repair and enhanced the proliferation rate and clonogenic capacity of aBM-MSC. Notably, Nanog enhanced the myogenic differentiation potential and reversed the effects of organismal aging on the contractile function of aBM-MSC to a similar level as that of neonatal (n)BM-MSC. The effect of Nanog on contractility was, in part, mediated through activation of the TGF-b pathway by diffusible factors secreted in the conditioned medium of Nanog-expressing BM-MSC. In addition, Nanog reversed senescence-dependent decline of alpha-smooth muscle actin (α-SMA) by synergizing with the TGF-b1 pathway and upregulating serum response factor (SRF). Overall, our results suggest that Nanog may be used to overcome the effects of organismal aging on aBM-MSC, thereby increasing the potential of MSC from aged donors for cellular therapy and tissue regeneration.