{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T01:52:49Z","timestamp":1781661169009,"version":"3.54.5"},"reference-count":41,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,4,27]],"date-time":"2025-04-27T00:00:00Z","timestamp":1745712000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Low dose methotrexate (LD\u2010MTX) remains the gold standard in rheumatoid arthritis (RA) therapy. Multiple mechanisms on a variety of immune cells contribute to the anti\u2010inflammatory effects of LD\u2010MTX. Inflammatory signaling is deeply implicated in hematopoiesis by regulating hematopoietic stem and progenitor cell (HSPC) fate decisions; raising the question of whether HSPC are also modulated by LD\u2010MTX. This is the first study to characterize the effects of LD\u2010MTX on HSPC. CD34\n                    <jats:sup>+<\/jats:sup>\n                    HSPC were isolated from healthy donors' non\u2010mobilized peripheral blood. Resting and\/or cycling HSPCs were treated with LD\u2010MTX [dose equivalent to that used in RA patients]. Flow cytometry was performed to assess HSPC viability, cell cycle, surface abundance of reduced folate carrier 1 (RFC1), proliferation, reactive oxygen species (ROS) levels, DNA double\u2010strand breaks, p38 activation, and CD34\n                    <jats:sup>+<\/jats:sup>\n                    subpopulations. HSPC clonogenicity was tested in colony\u2010forming cell assays. Our results indicate that in cycling HSPC, membrane RFC1 is upregulated and, following LD\u2010MTX treatment, they accumulate more intracellular MTX than resting HSPC. In cycling HSPC, LD\u2010MTX inhibits HSPC expansion by promoting S\u2010phase cell\u2010cycle arrest, increases intracellular HSPC ROS levels and DNA damage, and reduces HSPC viability. Those effects involve the activation of the p38 MAPK pathway and are rescued by folinic acid. The effects of LD\u2010MTX are more evident in CD34\n                    <jats:sup>+<\/jats:sup>\n                    \u2009CD38High progenitors. In non\u2010cycling HSPC, LD\u2010MTX also reduces the proliferative response while preserving their clonogenicity. In summary, HSPC uptake LD\u2010MTX differentially according to their cycling state. In turn, LD\u2010MTX results in reduced proliferation and the preservation of HSPC clonogenicity.\n                  <\/jats:p>","DOI":"10.1111\/cts.70233","type":"journal-article","created":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T00:08:24Z","timestamp":1745798904000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Low Dose Methotrexate Has Divergent Effects on Cycling and Resting Human Hematopoietic Stem and Progenitor Cells"],"prefix":"10.1111","volume":"18","author":[{"given":"Maximilien","family":"Lora","sequence":"first","affiliation":[{"name":"The Research Institute of the McGill University Health Centre (RI\u2010MUHC)  Montreal Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. A.","family":"M\u00e9nard","sequence":"additional","affiliation":[{"name":"Professor Emeritus Division of Rheumatology, Department of Medicine McGill University and RI\u2010MUHC  Montreal Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6048-4631","authenticated-orcid":false,"given":"Anastasia","family":"Nijnik","sequence":"additional","affiliation":[{"name":"Department of Physiology; McGill Research Centre on Complex Traits McGill University  Montreal Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4429-0110","authenticated-orcid":false,"given":"David","family":"Langlais","sequence":"additional","affiliation":[{"name":"Research Centre on Complex Traits, Dahdaleh Institute of Genomic Medicine, Department of Human Genetics, Department of Microbiology and Immunology McGill University  Montreal 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