Dynamic cell contacts between periportal mesenchyme and ductal epithelium act as a rheostat for liver cell proliferation.
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ABSTRACT:
SUBMITTER: Cordero-Espinoza L
PROVIDER: S-EPMC8577825 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Liver epithelial cells –hepatocytes and bile duct cells– intermingle with a microenvironment of endothelial cells, macrophages and fibroblasts to form the functional unit of the tissue. In homeostasis, the liver epithelium self-renews slowly, yet it is capable of remarkable regeneration following damage. We have shown that liver ductal cells can be expanded in vitro under defined medium to form 3D epithelial 'liver organoids' that recapitulate many aspects of the regeneration process in vitro, yet lack stromal cell components. Here, we describe that a subpopulation of portal mesenchymal cells expressing Sca1 and Pdgfra, exerts a dual effect on the proliferative capacity of ductal cells. On one hand, it supports liver organoid formation and expansion in the absence of exogenous growth factors and independently of cell-to-cell contact. However, when Ductal cells and SCA1+ mesenchymal cells establish physical interaction following a microfluidics encapsulation that enables the cells to self-organize into chimeric organoid structures, cell proliferation is abolished in a mesenchymal-dose dependent manner. We found that it is the ratio between mesenchyme and epithelial cells and not their absolute values that determines the net outcome of ductal proliferation both in vitro, and in vivo, during the different phases of liver regeneration. The mechanism by which Sca1+ mesenchymal cells regulate ductal cell proliferation dynamics is mediated, at least in part, by Notch cell-cell contact inhibition. Our findings underscore how the relative ratio and distribution of cell-cell contacts between the epithelium and its mesenchymal microenvironment are key regulatory processes during the dynamic regulation of tissue regeneration.
2021-11-30 | GSE140697 | GEO
Project description:The ratio of periportal mesenchyme to ductal epithelium acts as a proliferative rheostat in liver regeneration
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Project description:BACKGROUND& AIMS: Embryonic biliary precursor cells form a periportal sheet called the ductal plate, which is progressively remodeled to generate intrahepatic bile ducts. A limited number of ductal plate cells participate in duct formation; those not involved in duct development are believed to involute by apoptosis. Moreover, cells that express the SRY-related HMG box transcription factor 9 (SOX9), which include the embryonic ductal plate cells, were proposed to continuously supply the liver with hepatic cells. We investigated the role of the ductal plate in hepatic morphogenesis.Apoptosis and proliferation were investigated by immunostaining of mouse and human fetal liver tissue. The postnatal progeny of SOX9-expressing ductal plate cells was analyzed after genetic labeling, at the ductal plate stage, by Cre-mediated recombination of a ROSA26RYFP reporter allele. Inducible Cre expression was induced by SOX9 regulatory regions, inserted in a bacterial artificial chromosome. Livers were studied from mice under normal conditions and during diet-induced regeneration.Ductal plate cells did not undergo apoptosis and showed limited proliferation. They generated cholangiocytes lining interlobular bile ducts, bile ductules, and canals of Hering, as well as periportal hepatocytes. Oval cells that appeared during regeneration also derived from the ductal plate. We did not find that liver homeostasis required a continuous supply of cells from SOX9-expressing progenitors.The ductal plate gives rise to cholangiocytes lining the intrahepatic bile ducts, including its most proximal segments. It also generates periportal hepatocytes and adult hepatic progenitor cells.
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