title: Concomitant activation of miR-107/PDCD10 and hypoxamir-210/Casp8ap2 and their role in cytoprotection during ischemic preconditioning of stem cells.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pathology, University of Cincinnati, Cincinnati, Ohio 45267, USA.
authors.forename: Ha Won
authors.initials: HW
authors.lastname: Kim
authors.forename: Faryal
authors.initials: F
authors.lastname: Mallick
authors.forename: Shazia
authors.initials: S
authors.lastname: Durrani
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ashraf
authors.forename: Shujia
authors.initials: S
authors.lastname: Jiang
authors.forename: Khawaja Husnain
authors.initials: KH
authors.lastname: Haider
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D019610:Cytoprotection; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D019194:Ischemic Preconditioning; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D051017:Apoptosis Regulatory Proteins; C546364:CASP8AP2 protein, rat; D002352:Carrier Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C546388:MIRN210 microRNA, rat; D035683:MicroRNAs; C549821:PDCD10 protein, rat; D012333:RNA, Messenger