{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T13:07:59Z","timestamp":1789477679042,"version":"build-2803163510"},"reference-count":21,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T00:00:00Z","timestamp":1772755200000},"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. Cell Dev. Biol."],"abstract":"<jats:p>\n                    Mesenchymal stromal cells (MSCs) have emerged as promising therapeutic agents for inflammatory diseases because of their potent immunomodulatory properties. Although acute inflammation transiently enhances MSC functionality, the impact of chronic inflammatory exposure remains poorly defined. In this study, we investigated the effects of sustained TNF-\u03b1 stimulation and indirect co-culture with M1 macrophages on MSC behavior. Comprehensive gene expression profiling was performed to assess the changes in immunoregulatory, apoptotic, and metabolic pathways. To determine functional reversibility, we also evaluated MSCs following the withdrawal of TNF-\u03b1. Short-term exposure led to upregulation of\n                    <jats:italic>Tgf-\u03b2<\/jats:italic>\n                    ,\n                    <jats:italic>Il-10<\/jats:italic>\n                    , and\n                    <jats:italic>Fasl<\/jats:italic>\n                    , whereas prolonged stimulation suppressed these genes and significantly increased the expression of immune checkpoint genes\n                    <jats:italic>Pd-1<\/jats:italic>\n                    and\n                    <jats:italic>Ctla-4<\/jats:italic>\n                    , indicative of an exhaustion-like phenotype. This phenotypic shift was associated with sustained NF-\u03baB activation, upregulation of\n                    <jats:italic>Stat3<\/jats:italic>\n                    and\n                    <jats:italic>Ap-1<\/jats:italic>\n                    , suppression of mTORC1\/2 components, decreased\n                    <jats:italic>Pd-l1<\/jats:italic>\n                    expression, and increased\n                    <jats:italic>Pd-1<\/jats:italic>\n                    expression, raising the possibility that PD-1 upregulation is associated with MSC dysfunction under chronic inflammatory stress. These findings revealed that prolonged stimulation (48\u00a0h) induces an exhaustion-like dysfunction state in MSCs, characterized by checkpoint activation, transcriptional repression, and metabolic dysfunction. PD-1 may serve as a biomarker associated with inflammation-induced MSC impairment.\n                  <\/jats:p>","DOI":"10.3389\/fcell.2026.1680076","type":"journal-article","created":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T06:43:14Z","timestamp":1772779394000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Prolonged TNF-\u03b1 stimulation induces a PD-1\u2013associated exhaustion-like phenotype in mesenchymal stromal cells"],"prefix":"10.3389","volume":"14","author":[{"given":"Naoya","family":"Matsunaga","sequence":"first","affiliation":[{"name":"Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences","place":["Okayama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kentaro","family":"Akiyama","sequence":"additional","affiliation":[{"name":"Department of Occlusal and Oral Functional Rehabilitation, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences","place":["Okayama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aung Ye","family":"Mun","sequence":"additional","affiliation":[{"name":"Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences","place":["Okayama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingling","family":"Zou","sequence":"additional","affiliation":[{"name":"Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences","place":["Okayama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuki","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences","place":["Okayama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruji","family":"Tagashira","sequence":"additional","affiliation":[{"name":"Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences","place":["Okayama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuo","family":"Kuboki","sequence":"additional","affiliation":[{"name":"Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences","place":["Okayama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1016\/j.stem.2012.03.007","article-title":"Mesenchymal-stem-cell-induced immunoregulation involves FAS-ligand-\/FAS-mediated T cell apoptosis","volume":"10","author":"Akiyama","year":"2012","journal-title":"Cell Stem Cell"},{"key":"B2","doi-asserted-by":"publisher","first-page":"4876","DOI":"10.4049\/jimmunol.1302750","article-title":"STAT3, STAT4, NFATc, and CTCF regulate PD-1 through multiple novel regulatory regions in murine T cells","volume":"192","author":"Austin","year":"2014","journal-title":"J. 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