Autophagy controls mesenchymal stem cell therapy in psychological stress colitis mice

Autophagy. 2021 Sep;17(9):2586-2603. doi: 10.1080/15548627.2020.1821547. Epub 2020 Sep 17.

Abstract

Mesenchymal stem cell transplantation (MSCT) has been applied to treat a variety of autoimmune and inflammatory diseases. Psychosocial stress can aggravate disease progression in chronic inflammatory patients. Whether psychological stress affects MSCT is largely unknown. In this study we show that psychological stress attenuates therapeutic effects of MSCT in a DSS-induced colitis mouse model by elevating the levels of exosomal Mir7k/mmu-let-7 k (microRNA 7 k) in circulation. Mechanistically, Mir7k inhibits STAT3 pathway in donor MSCs, leading to upregulated expression of BECN1 (beclin 1, autophagy related) and, thus, activation of macroautophagy/autophagy. Inhibition of autophagy by blocking Mir7k or activating STAT3 signaling can restore MSCT-mediated therapy in psychologically stressed colitis mice. Our study identifies a previously unknown role of autophagy in regulating MSCT therapy via exosomal miRNA Mir7k.Abbreviations: BafA1: bafilomycin A1; BECN1: beclin 1, autophagy related; DAI: disease activity index; DAPI: 4',6-diamidino-2-phenylindole; DSS: dextran sulfate sodium; GFP: green fluorescent protein; HAI: histological activity index; IFNG/IFN-γ: interferon gamma; IL10: interleukin 10; IL1RN/IL-1Rra: interleukin 1 receptor antagonist; KD: knockdown; miRNA: microRNA; MSCs: mesenchymal stem cells; MSCT: mesenchymal stem cell transplantation; NTA: nanoparticle tracking analysis; PGE2: prostaglandin E2; SD: standard deviation; siRNA: small-interfering RNA; STAT3: signal transducer and activator of transcription 3; TEM: transmission electron microscopy; TGFB1/TGF-β1: transforming growth factor, beta 1; Th17 cell: T helper cell 17; TNF/TNF-α: tumor necrosis factor; TNFAIP6/TSG6: tumor necrosis factor alpha induced protein 6; Tregs: regulatory T cells.

Keywords: Autophagy; Mir7k miRNA; colitis; exosomes; mesenchymal stem cell; psychological stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / genetics
  • Colitis* / chemically induced
  • Colitis* / therapy
  • Dextran Sulfate / adverse effects
  • Dextran Sulfate / metabolism
  • Disease Models, Animal
  • Humans
  • Mesenchymal Stem Cell Transplantation*
  • Mesenchymal Stem Cells*
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Stress, Psychological

Substances

  • MIRN7 microRNA, human
  • MicroRNAs
  • Dextran Sulfate

Grants and funding

This work was supported by Guangdong Financial Fund for High-Caliber Hospital Construction (174-2018-XMZC-0001-03-0125, D-07 to S.S., D-11 to X.K.); The Pearl River Talent Recruitment Program (2019ZT08Y485); Sun Yat-sen University Young Teacher Key Cultivation Project (18ykzd05 to X.K.); National Nature Science Foundation of China (No. 81970925); Program of China Scholarships Council (No. 201606380078); and the Natural Science Foundation of Guangdong Province (No. 2016A030313262).