Abstract | BACKGROUND:
Idiopathic pulmonary fibrosis (IPF) is an age-related disease with no cure. Mesenchymal stem cell (MSC)-based therapy has emerged as a novel strategy for IPF treatment. Nevertheless, MSCs derived from patients with IPF (IPF-MSCs) become senescent, thereby reducing their beneficial effects in IPF. MicroRNAs ( miRNAs) mediate the senescence of MSCs, but the underlying mechanisms are not fully understood. We investigated the mechanisms by which miR-199a-5p regulates IPF-MSC senescence and whether its inhibition could rejuvenate IPF-MSCs and enhance their therapeutic efficacy. METHODS: Control-MSCs and IPF-MSCs were isolated from the adipose tissue of age-matched healthy and IPF donors, respectively. Cell senescence was examined by senescence-associated β- galactosidase (SA-β-gal) staining. The level of miR-199a-5p was measured by RT-PCR. Autophagy was determined using a transmission electron microscope (TEM). The therapeutic efficacy of anti-miR-199a-5p-IPF-MSCs was assessed using a mouse model of bleomycin-induced lung fibrosis. RESULTS: Despite similar surface makers, IPF-MSCs exhibited increased cellular senescence and decreased proliferative capacity compared with control-MSCs. The expression of miR-199a-5p was significantly enhanced in the serum of IPF patients and IPF-MSCs compared with that of healthy donors and control-MSCs. The upregulation of miR-199a-5p induced senescence of control-MSCs, whereas the downregulation rescued IPF-MSC senescence. Mechanistically, miR-155-5p suppressed autophagy of MSCs via the AMPK signaling pathway by downregulating the expression of Sirtuin 1( Sirt1), resulting in cellular senescence. Accordingly, miR-155-5p inhibition promoted autophagy and ameliorated IPF-MSC senescence by activating the Sirt1/AMPK signaling pathway. Compared with IPF-MSCs, the transplantation of anti-miR-199a-5p-IPF-MSCs increased the ability to prevent progression of pulmonary fibrosis in bleomycin-treated mice. CONCLUSIONS: Our study shows that miR-199a-5p regulates MSC senescence in patients with IPF by regulating the Sirt1/AMPK signaling pathway and miR-199a-5p is a novel target to rejuvenate IPF-MSCs and enhance their beneficial effects.
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Authors | Linli Shi, Qian Han, Yimei Hong, Weifeng Li, Gencheng Gong, Jiangyu Cui, Mengmeng Mao, Xiaoting Liang, Bei Hu, Xin Li, Qun Luo, Yuelin Zhang |
Journal | Stem cell research & therapy
(Stem Cell Res Ther)
Vol. 12
Issue 1
Pg. 147
(02 25 2021)
ISSN: 1757-6512 [Electronic] England |
PMID | 33632305
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
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Topics |
- Aged
- Cellular Senescence
- Humans
- Idiopathic Pulmonary Fibrosis
(genetics, therapy)
- Mesenchymal Stem Cells
- MicroRNAs
(genetics)
- Sirtuin 1
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