Hypoxia-induced miR-210 modulates the inflammatory response and fibrosis upon acute ischemia
| Autor: | Gaia Spinetti, Mario Tirone, Pasquale Creo, Simona Greco, Matteo Carrara, Paola Fuschi, Davide Maselli, Carlo Gaetano, Massimiliano Mazzone, Biagina Maimone, Fabio Martelli, Christine Voellenkle, Germana Zaccagnini, Marialucia Longo |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Cancer Research Acute Disease Animals Bone Marrow Transplantation Fibrosis Hindlimb Inflammation Ischemia Mice Mice Inbred C57BL MicroRNAs Angiogenesis Immunology In situ hybridization Inbred C57BL Article 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine medicine QH573-671 business.industry Regeneration (biology) Cell Biology medicine.disease 030104 developmental biology medicine.anatomical_structure Cardiovascular diseases Cell culture 030220 oncology & carcinogenesis Cancer research Bone marrow medicine.symptom business Cytology |
| Zdroj: | Cell Death and Disease, Vol 12, Iss 5, Pp 1-14 (2021) Cell Death & Disease |
| ISSN: | 2041-4889 |
| Popis: | 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. ispartof: CELL DEATH & DISEASE vol:12 issue:5 ispartof: location:England status: published |
| Databáze: | OpenAIRE |
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