Linli Shi1,2, Qian Han3, Yimei Hong2, Weifeng Li2, Gencheng Gong3, Jiangyu Cui2, Mengmeng Mao3, Xiaoting Liang4, Bei Hu2, Xin Li5,6, Qun Luo7, Yuelin Zhang8,9. 1. The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510080, Guangdong, China. 2. Department of Emergency Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China. 3. Department of Respiratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, Guangzhou, Guangdong, China. 4. Institute of Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China. 5. The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510080, Guangdong, China. xlidoct@qq.com. 6. Department of Emergency Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China. xlidoct@qq.com. 7. Department of Respiratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, Guangzhou, Guangdong, China. luoqunx@163.com. 8. The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510080, Guangdong, China. zhangyuelin1999@163.com. 9. Department of Emergency Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China. zhangyuelin1999@163.com.
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.
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.
Authors: Tao Liu; Xiaorong Ma; Tianxiang Ouyang; Huiping Chen; Jun Lin; Jun Liu; Yan Xiao; Jie Yu; Yingying Huang Journal: Int J Biol Macromol Date: 2018-05-24 Impact factor: 6.953
Authors: Nahal Mansouri; Gareth R Willis; Angeles Fernandez-Gonzalez; Monica Reis; Sina Nassiri; S Alex Mitsialis; Stella Kourembanas Journal: JCI Insight Date: 2019-11-01
Authors: Y Meng; A Eirin; X-Y Zhu; H Tang; L J Hickson; A Lerman; A J van Wijnen; L O Lerman Journal: Cell Transplant Date: 2018-09-06 Impact factor: 4.064
Authors: Soudeh Ghafouri-Fard; Tayyebeh Khoshbakht; Bashdar Mahmud Hussen; Aria Baniahmad; Wojciech Branicki; Mohammad Taheri; Ahmad Eghbali Journal: Front Cell Dev Biol Date: 2022-07-05
Authors: Giulia Maria Stella; Vito D'Agnano; Davide Piloni; Laura Saracino; Sara Lettieri; Francesca Mariani; Andrea Lancia; Chandra Bortolotto; Pietro Rinaldi; Francesco Falanga; Cristiano Primiceri; Angelo Guido Corsico; Andrea Bianco Journal: Transl Lung Cancer Res Date: 2022-03
Authors: Jianyang Liu; Jialin He; Lite Ge; Han Xiao; Yan Huang; Liuwang Zeng; Zheng Jiang; Ming Lu; Zhiping Hu Journal: Stem Cell Res Ther Date: 2021-07-22 Impact factor: 6.832