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Neural progenitor cells-secreted exosomal miR-210 induced by hypoxia influences cell viability.

ABSTRACT: Hypoxia as a microenvironment is essential for the development of neural stem/progenitor cells (NSCs/NPCs). Our previous studies showed that mild hypoxia can promote proliferation of NPCs. However, the underlying mechanisms are remaining unknown. In the present study, we explored the impact of hypoxia on miR-210 secretion and its effect on cell viability. We found that short time or long time of hypoxia treatment could increase the expression of miR-210, but also promoted its secretion into the medium. The results of exosomes isolation and quantitative real-time PCR showed that hypoxia increased the levels of miR-210 in the exosome enriched from the medium. In addition, the secreted miR-210 can be absorbed by recipient NPCs. The resutls of cell viability assay showed that low levels of secreted miR-210 slightly increased cell viability of NPCs. In contrast, high levels of secreted miR-210 exhibited an inhibitory effect on cell viability. These effects were blocked by an miR-210-specific inhibitor. Taken together, hypoxia increased secretion of miR-210 in exosomes and exhibited a differential effect on cell viability of recipient NPCs.Video abstract: http:/links.lww.com/WNR/A588.

SUBMITTER: Zhao M

PROVIDER: S-EPMC7340230 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Neural progenitor cells-secreted exosomal miR-210 induced by hypoxia influences cell viability.

Zhao Ming M Gao Yan Y Wang Fei F Cheng Xiang X Zhao Tong T Zhao Yongqi Y Fan Ming M Zhu Lingling L

Neuroreport 20200801 11

Hypoxia as a microenvironment is essential for the development of neural stem/progenitor cells (NSCs/NPCs). Our previous studies showed that mild hypoxia can promote proliferation of NPCs. However, the underlying mechanisms are remaining unknown. In the present study, we explored the impact of hypoxia on miR-210 secretion and its effect on cell viability. We found that short time or long time of hypoxia treatment could increase the expression of miR-210, but also promoted its secretion into the ...[more]

PMID: 32590394

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Project description:Hypoxia-induced miR-210 is a crucial component of the tissue response to ischemia, stimulating angiogenesis and improving tissue regeneration. Previous analysis of miR-210 impact on the transcriptome in a mouse model of hindlimb ischemia showed that miR-210 regulated not only vascular regeneration functions, but also inflammation. To investigate this event, doxycycline-inducible miR-210 transgenic mice (Tg-210) and anti-miR-210 LNA-oligonucleotides were used. It was found that global miR-210 expression decreased inflammatory cells density and macrophages accumulation in the ischemic tissue. To dissect the underpinning cell mechanisms, Tg-210 mice were used in bone marrow (BM) transplantation experiments and chimeric mice underwent hindlimb ischemia. MiR-210 overexpression in the ischemic tissue was sufficient to increase capillary density and tissue repair, and to reduce inflammation in the presence of Wt-BM infiltrating cells. Conversely, when Tg-210-BM cells migrated in a Wt ischemic tissue, dysfunctional angiogenesis, inflammation, and impaired tissue repair, accompanied by fibrosis were observed. The fibrotic regions were positive for α-SMA, Vimentin, and Collagen V fibrotic markers and for phospho-Smad3, highlighting the activation of TGF-β1 pathway. Identification of Tg-210 cells by in situ hybridization showed that BM-derived cells contributed directly to fibrotic areas, where macrophages co-expressing fibrotic markers were observed. Cell cultures of Tg-210 BM-derived macrophages exhibited a pro-fibrotic phenotype and were enriched with myofibroblast-like cells, which expressed canonical fibrosis markers. Interestingly, inhibitors of TGF-β type-1-receptor completely abrogated this pro-fibrotic phenotype. In conclusion, a context-dependent regulation by miR-210 of the inflammatory response was identified. miR-210 expression in infiltrating macrophages is associated to improved angiogenesis and tissue repair when the ischemic recipient tissue also expresses high levels of miR-210. Conversely, when infiltrating an ischemic tissue with mismatched miR-210 levels, macrophages expressing high miR-210 levels display a pro-fibrotic phenotype, leading to impaired tissue repair, fibrosis, and dysfunctional angiogenesis.

Project description:Cardiac shock wave therapy (SWT) has been described as a novel therapeutic strategy that is able to alleviate myocardial ischemic injury. microRNA (miRNA/miR)‑210 plays a cytoprotective role in cardiomyocytes in response to hypoxia by regulating cell apoptosis. The aim of the present study was to investigate whether cardiac SWT could protect cardiomyocytes from hypoxia‑induced injury by regulating miR‑210 expression. The murine adult cardiomyocyte cell line HL‑1 was incubated for 5 h in hypoxic conditions, followed by reoxygenation for 12 h and treatment with SWT immediately following hypoxia in the present study. The cell viability was determined using an MTS assay. Western blot analyses were performed in order to detect cell signaling changes. Reactive oxygen species production was detected using dihydroethidium staining, and malondialdehyde levels were measured using the thiobarbituric acid method. miRNA and mRNA expression levels were confirmed via reverse transcription‑quantitative PCR. Apoptosis was evaluated by means of flow cytometry. HL‑1 cells were then transfected with miR‑210 mimics or inhibitors in order to alter miR‑210 expression levels, and the effects on HL‑1 cells were determined. Hypoxia led to elevated oxidative stress, enhanced cell apoptosis and upregulated miR‑210 expression levels in HL‑1 cells, while SWT could alleviate hypoxia‑induced cell injury and further promote miR‑210 expression. miR‑210 overexpression decreased apoptosis and oxidative stress during hypoxic stress in HL‑1 cells, whereas inhibition of miR‑210 increased cell apoptosis and promoted oxidative stress. Furthermore, miR‑210 inhibition could reverse the effects of SWT on HL‑1 cells. Finally, the mRNA analysis revealed that SWT significantly attenuated apoptosis‑inducing factor mitochondrion‑associated 3 and caspase 8 associated protein 2 mRNA expression levels in cardiomyocytes exposed to hypoxia, which were two targets of miR‑210. SWT could exert cardioprotective effects against hypoxia‑induced cardiac injury by modulating miR‑210.

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Neural progenitor cells-secreted exosomal miR-210 induced by hypoxia influences cell viability.

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Neural progenitor cells-secreted exosomal miR-210 induced by hypoxia influences cell viability.

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