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Mesenchymal stromal cells (MSCs) have shown therapeutic promise, but their mechanisms, particularly concerning T cell metabolism, remain incompletely defined. This study investigated whether human umbilical cord\u2010derived MSCs (hUC\u2010MSCs) ameliorate collagen\u2010induced arthritis (CIA) by modulating T cell metabolism and differentiation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      CIA was induced in DBA\/1 mice. Animals received PBS or hUC\u2010MSCs on day 28. Arthritis index (AI), joint histology, serum cytokines (TNF\u2010\u03b1, IL\u20106, IL\u201017, and TGF\u2010\u03b2), and metabolites (lactate and pyruvate) were assessed. Splenic T cell transcription factors (\n                      <jats:italic>FOXP3<\/jats:italic>\n                      ,\n                      <jats:italic>ROR\u03b3t<\/jats:italic>\n                      , and\n                      <jats:italic>PU.1<\/jats:italic>\n                      ) and glycolytic genes (\n                      <jats:italic>GLUT1<\/jats:italic>\n                      ,\n                      <jats:italic>G6PD<\/jats:italic>\n                      , and\n                      <jats:italic>PFKFB3<\/jats:italic>\n                      ) were analyzed by real\u2010time quantitative polymerase chain reaction (RT\u2010qPCR) and western blot.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , human CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells were cocultured with hUC\u2010MSCs under T\u2010helper 17 (Th17)\u2010polarizing conditions. T cell subsets, glycolytic metabolites, and gene\/protein expression were evaluated by flow cytometry, colorimetric assays, RT\u2010qPCR, and western blot.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      MSC treatment significantly attenuated arthritis severity, joint destruction, and splenomegaly in CIA mice. It reduced serum pro\u2010inflammatory cytokines and normalized elevated lactate and pyruvate levels. In the spleen, MSCs suppressed\n                      <jats:italic>ROR\u03b3t<\/jats:italic>\n                      and\n                      <jats:italic>PU.1<\/jats:italic>\n                      while enhancing\n                      <jats:italic>FOXP3<\/jats:italic>\n                      expression, and downregulated\n                      <jats:italic>GLUT1<\/jats:italic>\n                      and\n                      <jats:italic>G6PD<\/jats:italic>\n                      mRNA. Positive correlations were found between glycolytic markers (\n                      <jats:italic>GLUT1<\/jats:italic>\n                      and\n                      <jats:italic>G6PD<\/jats:italic>\n                      ) and pro\u2010inflammatory transcription factors (\n                      <jats:italic>ROR\u03b3t<\/jats:italic>\n                      and\n                      <jats:italic>PU.1<\/jats:italic>\n                      ), and between serum lactate and inflammatory cytokines.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , hUC\u2010MSCs directly inhibited Th17 differentiation and promoted Treg generation in human CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells. This metabolic reprogramming was functionally coupled to a shift in T cell differentiation: a suppression of pro\u2010inflammatory Th17 cells and a promotion of regulatory T (Treg) generation in human CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells. This was accompanied by reduced lactate production and significant downregulation of\n                      <jats:italic>GLUT1<\/jats:italic>\n                      ,\n                      <jats:italic>G6PD<\/jats:italic>\n                      , and\n                      <jats:italic>PFKFB3<\/jats:italic>\n                      at both mRNA and protein levels.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>hUC\u2010MSCs ameliorate CIA by restoring the Th17\/Treg balance through metabolic reprogramming of T cells, specifically by suppressing glycolysis. This immunometabolic mechanism highlights the therapeutic potential of MSCs in RA.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1155\/jimr\/1862250","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T04:24:52Z","timestamp":1780979092000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Metabolic Reprogramming of T Cells by MSCs Rebalances Th17\/Treg Axis to Attenuate Collagen\u2010Induced 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