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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,5,26]]},"abstract":"<jats:p>Fibroblasts are key potentiators of chronic disease pathophysiology. Despite their established roles in promoting pathological inflammation and tissue remodeling, activated myofibroblasts are generally characterized as a single, homogeneous cell population, obscuring critical functional distinctions. Defining the cell states, their molecular regulators, and restricted markers is critical to developing effective therapies for the treatment of fibrosis. Here, using a human lung stromal cell atlas of idiopathic pulmonary fibrosis, we identify two myofibroblast transcriptional states associated with distinct predicted biological function, regulation, and cell surface marker expression. We identify fibroblast-specific TGFb signaling as the key regulator of the mechanistic switch from a wound healing\u2013associated and proliferative to a profibrotic myofibroblast. Further, we elucidate conserved TGFb-dependent and suppressed gene expression programs that define these states. Our findings reveal that LRRC15 is highly restricted to myofibroblasts that primarily express an extracellular matrix-remodeling gene program and illuminate that this key cell state can differentiate in the absence of an obligate inflammatory precursor intermediate. Last, we apply machine learning using a human single-cell foundation model to demonstrate broad applicability of the biology described herein to human chronic disease.<\/jats:p>","DOI":"10.1073\/pnas.2536550123","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T17:36:40Z","timestamp":1779298600000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":4,"title":["TGFb signaling instructs a conserved fibrosis-associated cell state marked by LRRC15"],"prefix":"10.1073","volume":"123","author":[{"given":"Justin A.","family":"Shyer","sequence":"first","affiliation":[{"name":"Genentech Research and Early Development, Genentech, Inc.","place":["South San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabien","family":"Wehbe","sequence":"additional","affiliation":[{"name":"Roche Informatics, F. 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