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Survival and proliferation of liver stem/progenitor cells by liver endothelial cells

ABSTRACT: Adult liver stem/progenitor cells (LPCs) exhibit robust proliferation upon impaired hepatocyte-mediated liver regeneration. However, the regenerative capacity becomes compromised in chronic liver diseases. Consequently, the promotion of liver regeneration through the utilization of LPCs emerges as a promising alternative therapeutic strategy for patients with chronic liver diseases. LPCs can be massively expanded in vitro as self-renewing organoids, however, lack of the niche cell interactions with LPCs is a major limitation. In this study, we highlight the role of liver endothelial cells (LiECs), as a part of LPC niche cells, in supporting the hepatobiliary organoids (HOs) in long-term culture even in the absence of key growth factors, such as Wnt agonists. Furthermore, LiECs altered the gene expression profile of HOs involved in inflammation, migration, extracellular matrix organization, and receptor signaling pathway through paracrine factors. Our findings expand the role of LiECs for regulating stemness of LPCs and provide a new organoid co-culture model using reduced growth medium.

ORGANISM(S): Mus musculus

PROVIDER: GSE259435 | GEO | 2025/02/10

REPOSITORIES: GEO

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Project description:We previously showed that severe liver diseases are characterized by expansion of liver progenitor cells (LPC), which correlates with disease severity. However, the origin and role of LPC in liver physiology and in the hepatic response to injury remains a contentious topic. We have now used genetic lineage tracing of Hnf1Î²-expressing biliary duct cells to assess their contribution to LPC expansion and hepatocyte generation during normal liver homeostasis, and following different types of liver injury. We found that ductular reaction cells in human cirrhotic livers express HNF1Î². However, HNF1Î² expression was not present in newly generated EpCAM-positive hepatocytes. Using a tamoxifen-inducible Hnf1Î²CreER/R26RYFP/LacZ mouse, we show that there is no contribution of the biliary epithelium to hepatocyte turnover during liver homeostasis in healthy mice. Moreover, after loss of liver mass, Hnf1Î²+ LPC did not contribute to hepatocyte regeneration. We also assessed the contribution of Hnf1Î²+ cells following acute and repeated liver injury. All animal models showed expansion of LPC, as assessed by immunostaining and gene expression profile of sorted YFP-positive cells. A contribution of Hnf1Î²+ LPC to hepatocyte generation was not detected in animal models of liver injury with preserved hepatocyte regenerative potential such as acute acetaminophen, carbon tetrachloride injury, or chronic diethoxycarbonyl-1,4-dihydro-collidin (DDC)-diet. However, in mice fed with choline-deficient ethionine-supplemented (CDE)-diet, which causes profound hepatocyte damage and arrest, a small number of hepatocytes were derived from Hnf1Î²+ cells. Conclusion: Hnf1Î²+ cells do not participate in hepatocyte turnover in the healthy liver or during liver regeneration after partial hepatectomy. After liver injury, LPC arise from the biliary duct epithelium, which gives rise to a limited number of hepatocytes only when hepatocyte regeneration is compromised. Transcriptomic profile using MoGeneST-2.0 chip from 3 samples of YFP+ CDE, 3 samples of YFP+ DDC, 2 samples of YFP+ UTR and 3 samples YFP-

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Survival and proliferation of liver stem/progenitor cells by liver endothelial cells

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