{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T19:02:23Z","timestamp":1789412543913,"version":"build-2803163510"},"reference-count":50,"publisher":"American Society for Clinical Investigation","issue":"18","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":49,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["WE 5009\/9-1,WE 5009\/12-1,WE 5009\/15-1,DO 373\/24-1"],"award-info":[{"award-number":["WE 5009\/9-1,WE 5009\/12-1,WE 5009\/15-1,DO 373\/24-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Chinese-German Cooperation Group projects","award":["GZ 1517"],"award-info":[{"award-number":["GZ 1517"]}]},{"name":"Chinese-German Mobility Programme","award":["M-0099"],"award-info":[{"award-number":["M-0099"]}]},{"name":"Bundesministerium f\u00fcr Forschung, Technologie und Raumfahrt-PTJ","award":["031L0257A,031L0314A"],"award-info":[{"award-number":["031L0257A,031L0314A"]}]},{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"crossref","award":["202106320043"],"award-info":[{"award-number":["202106320043"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,15]]},"abstract":"<jats:p>\n                    When massive hepatic necrosis\u2013associated (MHN-associated) acute liver failure (ALF) occurs following severe damage, liver progenitor cells (LPCs) exit quiescence and enter differentiation programs during which they acquire hepatocyte-like functions. How LPCs maintain quiescence under physiological conditions and orchestrate activation following MHN remains largely unknown. We elucidate an essential role of TGF-\u03b2 in regulating LPC quiescence and activation. Spatial transcriptomics and single-cell sequencing revealed that LPCs receive multiple signals, particularly TGF-\u03b2, HGF, and EGF, from surrounding hepatic stellate cells and macrophages in patients and zebrafish with MHN-induced ALF. Physiologically, TGF-\u03b2 inhibits LPC proliferation by blocking G1-to-S phase transition, an effect reversed by\n                    <jats:italic>Smad7<\/jats:italic>\n                    overexpression in a murine injury model. We observed extensive LPC proliferation in patients with ALF despite strong TGF-\u03b2\/phosphorylated SMAD signaling. Immunostaining revealed concurrent activation of HGF\/MET, EGF\/EGFR, and downstream STAT3\/ERK pathways in LPCs. In vitro, HGF or EGF overcame TGF-\u03b2\u2013mediated growth arrest and promoted LPC proliferation. Beyond acting as a mitogen, HGF additionally induced hepatocyte gene programs (e.g.,\n                    <jats:italic>Hnf4a<\/jats:italic>\n                    ,\n                    <jats:italic>Hnf1a<\/jats:italic>\n                    ) in LPCs. Strikingly, TGF-\u03b2 signaling was required for HGF-dependent hepatocyte gene induction, indicating a dual role in restraining LPC proliferation and promoting functional maturation. These findings position TGF-\u03b2 as a context-dependent determinant of LPC activation and lineage specification during ALF.\n                  <\/jats:p>","DOI":"10.1172\/jci199913","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T16:01:00Z","timestamp":1785254460000},"source":"Crossref","is-referenced-by-count":0,"title":["TGF-\u03b2 serves as a critical signaling determinant of liver progenitor cell activation and function"],"prefix":"10.1172","volume":"136","author":[{"given":"Chenhao","family":"Tong","sequence":"first","affiliation":[{"name":"Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany."},{"name":"Hepatopancreatobiliary Surgery Department, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, 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