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Human umbilical cord-derived mesenchymal stem cell-exosomal miR-627-5p ameliorates non-alcoholic fatty liver disease by repressing FTO expression

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Abstract

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disorders. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs)-based therapy is currently considered to be an effective treatment for NAFLD. The present study aimed to determine whether hUC-MSCs-exosomes have a hepatoprotective effect on NAFLD. We constructed NAFLD rat model by high-fat high-fructose feeding. Liver cells (L-O2) were treated with palmitic acid (PA) to mimic NAFLD model. NAFLD rats and PA-treated L-O2 cells were treated with hUC-MSCs-exosomes, and then we determined the influence of exosomes on liver damage and glucose and lipid metabolism in vivo and in vitro. We found that hUC-MSCs-exosomes exhibited an up-regulation of miR-627-5p. Exosomal miR-627-5p promoted cell viability and repressed apoptosis of PA-treated L-O2 cells. Exosomal miR-627-5p also enhanced the expression of G6Pc, PEPCK, FAS and SREBP-1c and suppressed PPARα expression in PA-treated L-O2 cells. Moreover, miR-627-5p interacted with fat mass and obesity-associated gene (FTO) and inhibited FTO expression in L-O2 cells. MiR-627-5p-enriched exosomes improved glucose and lipid metabolism in L-O2 cells by targeting FTO. In vivo, exosomal miR-627-5p ameliorated insulin tolerance, liver damage, glucose and lipid metabolism and reduced lipid deposition in NAFLD rats. Exosomal miR-627-5p also reduced body weight, liver weight, and liver index (body weight/liver weight) in NAFLD rats. In conclusion, these data demonstrate that HUC-MSCs-derived exosomal miR-627-5p improves glucose and lipid metabolism and alleviate liver damage by repressing FTO expression, thereby ameliorating NAFLD progression. Thus, hUC-MSCs-exosomes may be a potential treatment for NAFLD.

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Acknowledgements

This study was supported by the National Key R&D Program of China, Synthetic Biology Research (No. 2019YFA0904500); the National Natural Science Foundation of China (No. 81860151); the Key R&D Program of Jiangxi Province (No. 20192BBG70027).

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Authors and Affiliations

  1. Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Donghu District, Nanchang, 330006, China

    Lidan Cheng, Peng Yu, Fangfang Li, Xueling Jiang, Xiaojuan Jiao, Yunfeng Shen & Xiaoyang Lai

  2. Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang, 330006, China

    Lidan Cheng, Peng Yu, Fangfang Li, Xueling Jiang, Xiaojuan Jiao, Yunfeng Shen & Xiaoyang Lai

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  1. Lidan Cheng
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Correspondence to Yunfeng Shen or Xiaoyang Lai.

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13577_2021_593_MOESM1_ESM.tif

Supplementary Fig. 1 The body weight, liver weight, liver index and lipid deposition of NAFLD rats. Exosomes were isolated form hUC-MSCs following transfection of miR-627-5p inhibitor or inhibitor NC (miR-627-5pI-Exo, NCI-Exo). NAFLD rat model was constructed by HFHF feeding, followed by the exosome treatment. The body weight (A), liver weight (B) and liver index (C) of rats were measured. (D) The quantitative data of Oil Red O staining was presented. ***P < 0.001 vs. Normal; ##P < 0.01, ###P < 0.001 vs. Model; $P < 0.05, $$P < 0.01, $$$P < 0.001 vs. NCI-Exo (TIF 204 KB)

13577_2021_593_MOESM2_ESM.tif

Supplementary Fig. 2 The insulin levels of NAFLD rats. Exosomes were isolated form hUC-MSCs following transfection of miR-627-5p inhibitor or inhibitor NC (miR-627-5pI-Exo, NCI-Exo). NAFLD rat model was constructed by HFHF feeding, followed by the exosome treatment. The insulin levels of rats were detected by ELISA. ***P < 0.001 vs. Normal; ##P < 0.01 vs. Model; $P < 0.05 vs. NCI-Exo (TIF 118 KB)

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Cheng, L., Yu, P., Li, F. et al. Human umbilical cord-derived mesenchymal stem cell-exosomal miR-627-5p ameliorates non-alcoholic fatty liver disease by repressing FTO expression. Human Cell 34, 1697–1708 (2021). https://doi.org/10.1007/s13577-021-00593-1

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