ArticleStem cell research & therapy2019
Synergistic modulation of signaling pathways to expand and maintain the bipotency of human hepatoblasts.
Article in Stem cell research & therapy, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 28 citations in OpenAlex.
- Generation and applications of an expandable and mature hiPSC-derived liver organoid.Acta pharmaceutica Sinica. B · 2025Article
- Review
- Distinct Roles of Matrigel Enabled the Production of Expandable Hepatoblast and Polarized Hepatocyte Organoids from Human Embryonic Stem Cells under 3-Dimensional Suspension Conditions.Biomaterials research · 2025Article
- Chemical approaches targeting the hurdles of hepatocyte transplantation: mechanisms, applications, and advances.Frontiers in cell and developmental biology · 2024Review
- Establishing extended pluripotent stem cells from human urine cells.Cell & bioscience · 2023Article
- Article
- Pluripotent Stem Cell-derived Strategies to Treat Acute Liver Failure: Current Status and Future Directions.Journal of clinical and translational hepatology · 2022Review
- Efficiently generate functional hepatic cells from human pluripotent stem cells by complete small-molecule strategy.Stem cell research & therapy · 2022Article
- Robust expansion and functional maturation of human hepatoblasts by chemical strategy.Stem cell research & therapy · 2021Article
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Authors and funding
15 authors at 6 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe limited proliferative ability of hepatocytes is a major limitation to meet their demand for cell-based therapy, bio-artificial liver device, and drug tests. One strategy is to amplify cells at the hepatoblast (HB) stage. However, expansion of HBs with their bipotency preserved is challenging. Most HB expansion methods hardly maintain the bipotency and also lack functional confirmation.
methodsOn the basis of analyzing and manipulating related signaling pathways during HB (derived from human induced pluripotent stem cells, iPSCs) differentiation and proliferation, we established a specific chemically defined cocktails to synergistically regulate the related signaling pathways that optimize the balance of HB proliferation ability and stemness maintenance, to expand the HBs and investigate their capacity for injured liver repopulation in immune-deficient mice.
resultsWe found that the proliferative ability progressively declines during HB differentiation process. Small molecule activation of Wnt or inhibition of TGF-β pathways promoted HB proliferation but diminished their bipotency, whereas activation of hedgehog (HH) signaling stimulated proliferation and sustained HB phenotypes. A cocktail synergistically regulating the BMP/WNT/TGF-β/HH pathways created a fine balance for expansion and maintenance of the bipotency of HBs. After purification, colony formation, and expansion for 20 passages, HBs retained their RNA profile integrity, normal karyotype, and ability to differentiate into mature hepatocytes and cholangiocytes. Moreover, upon transplantation into liver injured mice, the expanded HBs could engraft and differentiate into mature human hepatocytes and repopulate liver tissue with restoring hepatocyte mass.
conclusionOur data contribute to the understanding of some signaling pathways for human HB proliferation in vitro. Simultaneous BMP/HGF induction, activation of Wnt and HH, and inhibition of TGF-β pathways created a reliable method for long-term stable large-scale expansion of HBs to obtain mature hepatocytes that may have substantial clinical applications.
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