Dataset Information

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.

SUBMITTER: Kim HW

PROVIDER: S-EPMC3423870 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Publications

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

Kim Ha Won HW Mallick Faryal F Durrani Shazia S Ashraf Muhammad M Jiang Shujia S Haider Khawaja Husnain KH

Antioxidants & redox signaling 20120523 8

<h4>Aims</h4>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.<h4>Results</h4>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 ((P ...[more]

PMID: 22482882

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Project description:Background and aimHypoxic-ischemic encephalopathy (HIE) is a disorder featured by hypoxic and ischemic damages during the perinatal period and its high mortality (i.e., 15%-20%) could be partly attributed to late diagnosis. Therefore, miR-210 and miR-374a were investigated to find if they could improve the diagnostic values of S100B protein and neuron-specific enolase (NSE) for HIE.MethodsAltogether 167 HIE newborns and 82 healthy newborns were recruited, and their blood were sampled for determining the levels of biomarkers. Specifically, S100B protein and NSE levels were detected based on the enzyme-linked immunosorbent assay (ELISA) kit, while the expressions of miR-210 and miR-374a were quantified by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Moreover, the receiver operating characteristic (ROC) curves were established to assess the diagnostic values of the above biomarkers for HIE. Finally, the correlation analysis between miR-210/miR-374 and Neonatal Behavioral Neurological Assessment (NBNA) scoring or Gesell intellectual development were also conducted.ResultsThe levels of miR-210, miR-374a, S100B protein, and NSE were significantly distinct between HIE patients and healthy newborns (p < .05). Besides, miR-210 (rs = .573), miR-374a (rs = .651), NSE level (rs = -.622), and S100B level (rs = -.55) were all, respectively, correlated with NBNA scoring with statistical significance (p < .05). Furthermore, it was revealed that the combined diagnosis of miR-210, miR-374a, S100B protein, and NSE could obtain the highest accuracy regarding pairs of mild HIE versus moderate HIE (AUC = 0.898), moderate HIE versus severe HIE (AUC = 0.922), mild HIE versus severe HIE (AUC = 0.996), and HIE versus control (AUC = 0.960). More than that, the four molecules were also remarkably associated with Gesell intellectual development (p < .05).ConclusionMiR-210 and miR-374a could help to elevate the diagnostic value and prognostic prediction of S100B protein and NSE for HIE.

Project description:Sepsis is a common and life-threatening systemic disorder, often leading to acute injury of multiple organs. Here, we show that remote ischemic preconditioning (rIPC), elicited by brief episodes of ischemia and reperfusion in femoral arteries, provides protective effects against sepsis-induced acute kidney injury (AKI). Methods: Limb rIPC was conducted on mice in vivo 24 h before the onset of cecal ligation and puncture (CLP), and serum exosomes derived from rIPC mice were infused into CLP-challenged recipients. In vitro, we extracted and identified exosomes from differentiated C2C12 cells (myotubes) subjected to hypoxia and reoxygenation (H/R) preconditioning, and the exosomes were administered to lipopolysaccharide (LPS)-treated mouse tubular epithelial cells (mTECs) or intravenously injected into CLP-challenged miR-21 knockout mice for rescue experiments. Results: Limb rIPC protected polymicrobial septic mice from multiple organ dysfunction, systemic accumulation of inflammatory cytokines and accelerated parenchymal cell apoptosis through upregulation of miR-21 in a hypoxia-inducible factor 1α (HIF-1α)-dependent manner in the ischemic limbs of mice. However, in miR-21 knockout mice or mice that received HIF-1α siRNA injection into hind limb muscles, the organ protection conferred by limb rIPC was abolished. Mechanistically, we discovered that miR-21 was transported from preischemic limbs to remote organs via serum exosomes. In kidneys, the enhanced exosomal miR-21 derived from cultured myotubes with H/R or the serum of mice treated with rIPC integrated into renal tubular epithelial cells and then targeted the downstream PDCD4/NF-κB and PTEN/AKT pathways, exerting anti-inflammatory and anti-apoptotic effects and consequently attenuating sepsis-induced renal injury both in vivo and in vitro. Conclusion: This study demonstrates a critical role for exosomal miR-21 in renoprotection conferred by limb rIPC against sepsis and suggests that rIPC and exosomes might serve as the possible therapeutic strategies for sepsis-induced kidney injury.

Dataset Information

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

Aims

Results

Innovation

Conclusion

Publications

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

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