{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T09:51:35Z","timestamp":1791280295917,"version":"4.1.0"},"reference-count":82,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"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. Bioeng. Biotechnol."],"abstract":"<jats:p>\n                    Polytrauma, defined as life-threatening injuries to multiple organ systems with an Injury Severity Score greater than 16, presents significant challenges for fracture healing, with nonunion rates substantially higher than in isolated fractures. The systemic inflammatory response syndrome (SIRS) and subsequent immune dysregulation characteristic of polytrauma create a hostile microenvironment that impairs normal bone regeneration. Mesenchymal stromal cells (MSCs; also termed mesenchymal stem\/stromal cells) play critical roles in fracture healing through immunomodulation, osteogenic differentiation, and promotion of angiogenesis. However, emerging evidence suggests that MSC-mediated processes may be compromised in polytrauma settings. Importantly, direct evidence for endogenous MSC dysfunction in human polytrauma remains limited: much of the current understanding is inferred from isolated-fracture models,\n                    <jats:italic>in vitro<\/jats:italic>\n                    inflammatory-stimulation studies, and animal polytrauma systems rather than from controlled human trauma data. This review examines the mechanisms by which polytrauma is associated with disruption of MSC function, including altered macrophage polarization, excessive neutrophil activation, reduced regulatory T cell populations, and complement-mediated MSC injury. We synthesize the current understanding of MSC immunomodulatory effects in normal fracture healing and contrast this with their dysfunction in polytrauma, where MSCs adopt pro-inflammatory phenotypes and demonstrate impaired homing. Clinical applications of MSC-based therapies are discussed, including bone marrow aspirate concentrates and tissue-engineered constructs, alongside their potential for systemic immunomodulation in trauma patients. Throughout, we distinguish endogenous MSC behavior in polytrauma from exogenous MSC-based therapies, and we separate various MSC-based therapies as biologically and translationally distinct concepts. Finally, we outline critical knowledge gaps and propose future research directions, including development of representative polytrauma models, optimization of MSC delivery methods, and exploration of MSC-derived extracellular vesicles as therapeutic alternatives to improve outcomes in polytraumatized patients.\n                  <\/jats:p>","DOI":"10.3389\/fbioe.2026.1892227","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:59:06Z","timestamp":1791277146000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Mesenchymal stromal cells in polytrauma: from immune dysregulation to therapeutic potential"],"prefix":"10.3389","volume":"14","author":[{"given":"Charles S.","family":"Black","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery, UC Davis Health","place":["Sacramento, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milen","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, UC Davis Health","place":["Sacramento, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renato Miguel","family":"Reyes","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, UC Davis Health","place":["Sacramento, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Kent","family":"Leach","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, UC Davis Health","place":["Sacramento, CA, United States"]},{"name":"Department of Biomedical Engineering, University of California, Davis","place":["Davis, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, UC Davis Health","place":["Sacramento, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e5vard Jostein","family":"Haugen","sequence":"additional","affiliation":[{"name":"Department of Biomaterials, Institute of Clinical Dentistry, University of Oslo","place":["Oslo, Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thaqif","family":"El Khassawna","sequence":"additional","affiliation":[{"name":"Experimental Trauma Surgery, Justus-Liebig University Giessen","place":["Giessen, Germany"]},{"name":"School of Pharmacy, The University of Jordan","place":["Amman, Jordan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam","family":"Rahmati","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, UC Davis Health","place":["Sacramento, CA, United States"]},{"name":"Department of Biomaterials, Institute of Clinical Dentistry, University of Oslo","place":["Oslo, Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Augustine Mark","family":"Saiz","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, UC Davis Health","place":["Sacramento, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e0216862","DOI":"10.1371\/journal.pone.0216862","article-title":"Inflammatory response of mesenchymal stromal cells after in vivo exposure with selected trauma-related factors and polytrauma serum","volume":"14","author":"Amann","year":"2019","journal-title":"PLoS One"},{"key":"B2","doi-asserted-by":"publisher","first-page":"9759","DOI":"10.3390\/ijms21249759","article-title":"Clinical application of bone marrow mesenchymal stem\/stromal cells to repair skeletal tissue","volume":"21","author":"Arthur","year":"2020","journal-title":"Int. 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