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-1 alpha (HIF-1 alpha) in preconditioned mesenchymal stem cells ((MSC)-M-PC), which showed improved survival during subsequent exposure to 6 h of lethal anoxia (p < 0.05 vs. non-preconditioned MSC[non-PCMSC]). In silico analysis and luciferase activity assay confirmed programmed cell death-10 (PDCD10) as a putative target of miR-107 in (MSC)-M-PC, 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 (MSC)-M-PC. 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 (MSC)-M-PC survival under lethal anoxia. The transplantation of (MSC)-M-PC in an acute model of myocardial infarction showed a significantly improved survival of transplanted (MSC)-M-PC with concomitantly enhanced miR-107 expression in (MSC)-M-PC-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 (MSC)-M-PC 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. Antioxid. Redox Signal. 17, 1053-1065.