Concomitant activation of miR-107/PDCD10 and hypoxamir-210/Casp8ap2 and their role in cytoprotection during ischemic preconditioning of stem cells.

AIMS:To establish a functional link between microRNA-107 (miR-107) and stem cell survival during ischemic preconditioning (IPC) of stem cells with multiple cycles of brief anoxia/re-oxygenation (10 or 30 min, one to three cycles) and show that the cytoprotective effects were independent of hypoxamir-210. RESULTS:We demonstrated the induction of miR-107 in response to the IPC-induced activation of Akt/hypoxia inducible factor-1α (HIF-1α) in preconditioned mesenchymal stem cells ((PC)MSC), which showed improved survival during subsequent exposure to 6 h of lethal anoxia (p<0.05 vs. non-preconditioned MSC[(non-PC)MSC]). In silico analysis and luciferase activity assay confirmed programmed cell death-10 (PDCD10) as a putative target of miR-107 in (PC)MSC, which was significantly reduced during IPC and inversely related to stem cell survival under 6 h of lethal anoxia. Loss-of-function studies with miR-107 antagomir showed a significantly reduced survival of (PC)MSC. A comparison of miR-107 and miR-210 showed that both miRs participated independently via their respective putative target genes Pdcd10 and Casp8ap2. The simultaneous abrogation of Pdcd10 and Casp8ap2 had a stronger effect on (PC)MSC survival under lethal anoxia. The transplantation of (PC)MSC in an acute model of myocardial infarction showed a significantly improved survival of transplanted (PC)MSC with concomitantly enhanced miR-107 expression in (PC)MSC-transplanted animal hearts. INNOVATION:Cytoprotection afforded by IPC is regulated by miR-107 induction via Pdcd10 independent of miR-210/Casp8ap2 signaling, and the simultaneous abrogation miR-107/miR-210 has a stronger effect on the loss of (PC)MSC survival. CONCLUSION:IPC enhances stem cell survival via the combined participation of hypoxia responsive miRs miR-107 and miR-210 via their respective putative target genes Pdcd10 and Casp8ap2.

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