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Since its inception more than two decades ago, ischemic preconditioning (IP) is considered as the most powerful cytoprotective stimulus and is being devised as a potent strategy to promote stem cell survival post-engraftment in the infarcted heart 1. The elegant study from Hu and colleagues is a step forward towards the use of low oxygen culture conditions to trigger activation of survival signaling pathways in the cells before their engraftment in vivo 2. The authors showed significantly improved survival of the hypoxia (0.5% oxygen for 24 hours) treated mesenchymal stem cells post engraftment in the infarcted heart. Unlike many of the previous studies, an important aspect of the study protocol was cell engraftment during acute phase of myocardial infarction to assess the effectiveness of preconditioning approach. Acute phase engraftment exposed the engrafted cells to the harsh cytokine rich microenvironment of the infarcted myocardium which was aggravated even more due to the infiltration of inflammatory and progenitor cells as a part of the intrinsic repair process. The authors attributed the effectiveness of the hypoxic preconditioning approach to upregulation of hypoxia inducible factor-1α, a heterodimeric master switch of hypoxia responsive array of genes in the cells which enable the cells to acclimatize and survive in the low oxygen conditions. Although low level presence of HIF-1α has been reported in the cytoplasmic compartment of the cells grown under normoxia, hypoxia stabilizes HIF-1α against degradation and promotes its translocation to the nucleus where it forms functional complexes for gain-of-functions. As a part of our continuing endeavor to precondition donor cells for their better survival in the infarcted heart and that too with clinical relevance 3, we share our experience of extrapolating the classical IP strategy of exposing the cells to multiple sub-lethal ischemia/reoxygenation cycles of short duration to promote MSC survival (our unpublished data). This approach represents an extension of the one-time long-term exposure to sub-lethal hypoxia approach suggested by Hu et al 2. Our results showed significant upregulation of HIF-1α in Akt dependent manner in the cells preconditioned by 2 cycles I/R of 30 minutes each. These molecular events successfully attenuated donor cell attrition upon subsequent exposure to lethal ischemic insult. The participation of hypoxia associated microRNAs (miR), miR-107 and miR-210 4 downstream of HIF-1α in translation of cytoprotective effects of IP was another important observation of our study. HIF-1α specific RNA interference abrogated both miR-107 and miR-210 in the preconditioned cells transfected with HIF-1α specific siRNA with a concomitant increase in preponderance of apoptotic cells. Our in vivo experimental results in a rodent model of acute myocardial infarction showed that transplantation of preconditioned cells survived significantly better as compared with their non-preconditioned counterparts. Moreover, transplantation of preconditioned cells promoted miR-107 and -210 expression in the infarcted heart at the site of the cell graft. These novel findings necessitate more in-depth studies to elucidate if the of effect of IP can be duplicated by manipulation of the cells for hypoxia related miRNAs to promote donor cell survival.