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The ratio of periportal mesenchyme to ductal epithelium acts as a proliferative rheostat in liver regeneration

ABSTRACT: The ratio of periportal mesenchyme to ductal epithelium acts as a proliferative rheostat in liver regeneration

PROVIDER: PRJNA590528 | ENA |

REPOSITORIES: ENA

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The ratio of periportal mesenchyme to ductal epithelium acts as a proliferative rheostat in liver regeneration

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.

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WUSCHEL acts as a rheostat on the auxin pathway to maintain apical stem cells in Arabidopsis [RNA-seq]

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