{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T13:44:19Z","timestamp":1792071859984,"version":"4.4.0"},"reference-count":66,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,12,6]],"date-time":"2023-12-06T00:00:00Z","timestamp":1701820800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Mesenchymal stem cells (MSCs) can alleviate graft-versus-host disease (GVHD) in hematopoietic stem cell transplantation (HSCT). MSCs-derived exosomes (MEXs) can mirror the biological function of their parent cells. Whether MEXs can alleviate GVHD like their parent cells or not is unclear. In this study, we investigate the effects of MEXs on GVHD and graft-versus-leukemia (GVL) effect <jats:italic>in vitro<\/jats:italic> and in HSCT animal models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>MSCs were produced using bone marrow mononuclear cells (MNCs), and MEXs were separated from the supernatants of MSCs. Electron microscopy, western blot, and nanoparticle tracking analysis (NTA) were used to determine the characteristics of MEXs. The immunomodulatory function of MEXs and their effects on GVHD and GVL were examined <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Result<\/jats:title><jats:p>Like other cell-type derived exosomes, our data revealed that MEXs were also disc-shaped vesicles with a diameter of 100\u2013200 nm under electron microscopy and were positive for the exosomal hallmark proteins. MEXs can notably inhibit the expression of costimulatory molecules and functional cytokine secretion of dendritic cells (DCs). Meanwhile, MEXs can exert suppressive effects on T lymphocyte proliferation and activation. Moreover, MEXs can also encourage the polarization of macrophages toward the M2 type. In animal HSCT models, MEXs can promote the differentiation of Treg cells in spleens, decrease the GVHD score, increase the survival rate of mice, and preserve the cytotoxic antileukemia effects of CD8<jats:sup>+<\/jats:sup> T lymphocytes from recipient mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings showed that MEXs exert their effects by inhibiting the immunomodulatory function of DCs, macrophages, and T lymphocytes. In the animal model, MEXs ameliorate the clinical symptoms of GVHD, while maintaining the antitumor effects of CD8<jats:sup>+<\/jats:sup> T lymphocytes. Therefore, it can be inferred that MEXs can separate GVHD from GVL in HSCT. Our study suggests that MEXs have broad clinical application potential in the prevention and treatment of GVHD in HSCT in the near future.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1284936","type":"journal-article","created":{"date-parts":[[2023,12,6]],"date-time":"2023-12-06T08:33:40Z","timestamp":1701851620000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":24,"title":["Mesenchymal stem cell-derived exosomes can alleviate GVHD and preserve the GVL effect in allogeneic stem cell transplantation animal models"],"prefix":"10.3389","volume":"14","author":[{"given":"Yan","family":"Jiang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minghui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangbo","family":"Wan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siguo","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,12,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1126\/science.284.5411.143","article-title":"Multilineage potential of adult human mesenchymal stem cells","volume":"284","author":"Pittenger","year":"1999","journal-title":"Science"},{"key":"B2","doi-asserted-by":"publisher","first-page":"5","DOI":"10.3727\/096368910X","article-title":"Mesenchymal stem cells","volume":"20","author":"Ding","year":"2011","journal-title":"Cell Transplantation"},{"key":"B3","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1186\/scrt216","article-title":"Mesenchymal stem cells generate a CD4+CD25+Foxp3+ regulatory T cell population during the differentiation process of Th1 and Th17 cells","volume":"4","author":"Luz-Crawford","year":"2013","journal-title":"Stem Cell Res Ther"},{"key":"B4","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1186\/s13287-017-0499-0","article-title":"Effects of mesenchymal stem cells from human induced pluripotent stem cells on differentiation, maturation, and function of dendritic cells","volume":"8","author":"Gao","year":"2017","journal-title":"Stem Cell Res Ther"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1080\/14653240701452057","article-title":"MSC\u2013DC interactions: MSC inhibit maturation and migration of BM-derived DC","volume":"9","author":"Jung","year":"2007","journal-title":"Cytotherapy"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0902007","article-title":"Mesenchymal stem cells inhibit human Th17 cell differentiation and function and induce a T regulatory cell phenotype","volume":"185","author":"Ghannam","year":"2010","journal-title":"J Immunol (Baltimore Md 1950)"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0045272","article-title":"Mesenchymal stem cells repress Th17 molecular program through the PD-1 pathway","volume":"7","author":"Luz-Crawford","year":"2012","journal-title":"PLoS One"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-023-00949-7","article-title":"Mesenchymal stem cell-derived extracellular vesicles subvert Th17 cells by destabilizing ROR\u03b3t through posttranslational modification","volume":"55","author":"Jung","year":"2023","journal-title":"Exp Mol Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/bmt.2017.35","article-title":"Mesenchymal stromal cell infusion to treat steroid-refractory acute GvHD III\/IV after hematopoietic stem cell transplantation","volume":"52","author":"Dotoli","year":"2017","journal-title":"Bone Marrow Transpl"},{"key":"B10","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1186\/s13287-020-01592-z","article-title":"Guti\u00e9rrez-Pizarraya , Sanchez-Pernaute R. 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