{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:07:34Z","timestamp":1785431254071,"version":"3.56.0"},"posted":{"date-parts":[[2025,6,9]]},"group-title":"Developmental Biology","reference-count":42,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T00:00:00Z","timestamp":1749427200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"award":["DP1"],"award-info":[{"award-number":["DP1"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01"],"award-info":[{"award-number":["R01"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,6,8]]},"abstract":"<jats:p>\n                  The embryonic development of the liver is initiated by the emergence of hepatoblasts, originating from the ventral foregut endoderm adjacent to the heart. Here, we identify and characterize a previously unrecognized population of early hepatoblasts at the ventroposterior part of the emerging liver bud, traced from\n                  <jats:italic>Cdx2<\/jats:italic>\n                  -positive endoderm progenitors, which we term primitive hepatoblasts. Mouse and human single-cell transcriptomics reveals the expression of both canonical hepatoblast markers\n                  <jats:italic>TBX3<\/jats:italic>\n                  ,\n                  <jats:italic>FGB<\/jats:italic>\n                  , and\n                  <jats:italic>KRT8\/18<\/jats:italic>\n                  and primitive-specific mesenchymal markers\n                  <jats:italic>ID3<\/jats:italic>\n                  ,\n                  <jats:italic>VIM<\/jats:italic>\n                  , and\n                  <jats:italic>GATA4<\/jats:italic>\n                  . Lineage tracing revealed the notable contribution up to 12.6% of LIV2+ hepatoblasts at E11.5 but diminishes in late fetal and postnatal development. Epigenetic and functional perturbation studies further uncover that primitive hepatoblast emergence is primed by WNT-suppression on RA-permissive CDX2+FOXA2+ progenitors. Furthermore, human pluripotent stem cell-derived primitive hepatoblast-like cells secrete pleiotrophin and midkine to amplify hepatoblast populations and develop epithelial-mesenchymal hybrid tissues\n                  <jats:italic>in vivo<\/jats:italic>\n                  . Our results provide a new framework for understanding lineage heterogeneity during early hepatogenesis and offer revised insights into strategies to model normal and abnormal liver development.\n                <\/jats:p>","DOI":"10.1101\/2025.06.08.658502","type":"posted-content","created":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T05:30:22Z","timestamp":1749447022000},"source":"Crossref","is-referenced-by-count":0,"title":["Primitive Hepatoblasts Driving Early Liver Development"],"prefix":"10.64898","author":[{"given":"Kentaro","family":"Iwasawa","sequence":"first","affiliation":[{"name":"Division of Gastroenterology, Hepatology & Nutrition, Cincinnati Children\u2019s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA"},{"name":"Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children\u2019s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, 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