hUCMSC-derived exosomes protect against GVHD-induced endoplasmic reticulum stress in CD4+ T cells by targeting the miR-16-5p/ATF6/CHOP axis

• Published in: International immunopharmacology 2024-06, Vol.135, p.112315, Article 112315
• Main Authors: Li, Weihan, Si, Yaru, Wang, Yueming, Chen, Juntong, Huo, Xingyu, Xu, Pengzhan, Jiang, Bingzhen, Li, Zile, Shang, Kangdi, Luo, Qianqian, Xiong, Yanlian
• Format: Article
• Language: English
• Subjects: Activating Transcription Factor 6 - genetics; Activating Transcription Factor 6 - metabolism; Animals; Apoptosis; ATF6; CD4+ T cells; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cells, Cultured; Endoplasmic Reticulum Stress - immunology; ER stress; Exosomes - metabolism; Graft vs Host Disease - immunology; Graft vs Host Disease - prevention & control; GVHD; Humans; Mesenchymal Stem Cells - immunology; Mesenchymal Stem Cells - metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; MicroRNAs - genetics; MicroRNAs - metabolism; miR-16-5p; MSC exosomes; Signal Transduction; Transcription Factor CHOP - genetics; Transcription Factor CHOP - metabolism; Umbilical Cord - cytology
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2024.112315

•hUCMSC-Exo promotes the differentiation of CD4+IL-10+T cells.•hUCMSC-Exo suppresses ER stress of CD4+ T cells by transfer miR-16-5p.•hUCMSC-Exo suppresses apoptosis of CD4+ T cells.•hUCMSC-Exo alleviates oxidative stress and inflammatory response during GVHD. Exosomes generated from mesenchymal stem cells (MSCs) are thought to be a unique therapeutic strategy for several autoimmune deficiency illnesses. The purpose of this study was to elucidate the protective effects of human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-Exo) on CD4+ T cells dysfunction during graft-versus-host disease (GVHD) and to identify the underlying processes involved. Here, we showed that hUCMSC-Exo treatment can effectively attenuate GVHD injury by alleviating redox metabolism disorders and inflammatory cytokine bursts in CD4+ T cells. Furthermore, hUCMSC-Exo ameliorate ER stress and ATF6/CHOP signaling-mediated apoptosis in CD4+ T cells and promote the development of CD4+IL-10+ T cells during GVHD. Moreover, downregulating miR-16-5p in hUCMSC-Exo impaired their ability to prevent CD4+ T cells apoptosis and weakened their ability to promote the differentiation of CD4+IL-10+ T cells. Collectively, the obtained data suggested that hUCMSC-Exo suppress ATF6/CHOP signaling-mediated ER stress and apoptosis in CD4+ T cells, enhance the differentiation of CD4+IL-10+ T cells, and reverse the imbalance of immune homeostasis in the GVHD process by transferring miR-16-5p. Our study provided further evidence that GVHD patients can benefit from hUCMSC-Exo-mediated therapy.