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

Abstract

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.

• Authors: Ha Won Kim, Faryal Mallick, Shazia Durrani, Muhammad Ashraf, Shujia Jiang, Khawaja Husnain Haider
• Journal: Antioxidants & redox signaling (Antioxid Redox Signal) Vol. 17 Issue 8 Pg. 1053-65 (Oct 15 2012) ISSN: 1557-7716 [Electronic] United States
• PMID: 22482882 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Apoptosis Regulatory Proteins
• CASP8AP2 protein, rat
• Carrier Proteins
• Hypoxia-Inducible Factor 1, alpha Subunit
• MIRN210 microRNA, rat
• MicroRNAs
• PDCD10 protein, rat
• RNA, Messenger

Topics

• Animals
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Brain Ischemia (metabolism, pathology)
• Carrier Proteins (genetics, metabolism)
• Cell Survival
• Cytoprotection
• Female
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Ischemic Preconditioning
• Male
• Mesenchymal Stem Cells (metabolism, pathology)
• MicroRNAs (genetics, metabolism)
• RNA, Messenger (genetics, metabolism)
• Rats
• Rats, Inbred F344