Abstract 1280: Transcriptional Profiling Of Young And Old Mesenchymal Stem Cells For Their Response To Oxygen Deprivation And Myocardial Reparability
Background: Most clinical studies used autologous bone marrow stem cells (BMSCs) for myocardial repair in elderly patients. Accounting for the limited success in clinical studies, we hypothesized that aging impairs the reparability of BMSCs which limits their therapeutic efficacy.
Methods and Results: We compared MSCs from young (YngMSCs; 8–12 weeks) and old (OldMSCs; 24–26 weeks) rats for their responsiveness to anoxia and therapeutic potential. A significantly higher expression of angiogenic growth factors was observed by YngMSCs under anoxia as compared with OldMSCs, cultured either alone or in co-culture (Co-oldMSCs) with YngMSCs. Likewise, YngMSCs showed significantly higher ability to form tubular structures during Matrigel assay. LDH release assay showed that YngMSCs were more tolerant to apoptotic stimuli (glucose and serum starvation under anoxia) as compared with OldMSCs and Co-oldMSCs, with a possible role for pro-survival proteins p21 and p27 which showed increased gene expression (>8-fold and 13-fold respectively) in YngMSCs under anoxia as compared with OldMSCs. For in vivo studies, acute myocardial infarction model was developed in Fisher-344 rats (n=38). The animals were grouped to receive 70μl DMEM without cells (group-1) or containing 3×106 YngMSCs (PKH67 labeled; group-2), or OldMSCs (PKH26 labeled; group-3) and mixture of YngMSCs+OldMSCs (1.5×106 cells each, group-4). Histological studies revealed that by day-7, YngMSCs were already showing elongated morphology with orientation similar to the host muscle architecture. Transmission electron microscopy and confocal imaging after immuno-staining for vonWillebrand Factor-VIII, myosin heavy chain, cardiac actinin and connexin-43, showed superior angiomyogenic potential of YngMSCs. Echocardiography showed significantly improved indices of left ventricle contractile function in group-4.
Conclusions: Aging significantly weakened the responsiveness of OldMSCs to anoxia and their differentiation potential. Their reparability of infarcted heart was also impaired with aging which was not improved by the presence of YngMSCs. Hence, transplantation of stem cells from young donors should be considered for heart cell therapy in elderly patients for better prognosis.