Dynamic cell contacts between periportal mesenchyme and ductal epithelium act as a rheostat for liver cell proliferation.

Lucía Cordero-Espinoza,Florian Jug,Ross Dobie,Bernhard Strauss,Florian Hollfelder,Clare Pacini,Palle Serup,Nuno P Martins,Neil C Henderson,Timo N Kohler,Nicole Prior,German Belenguer,John R Wilson-Kanamori,Olga Sarlidou,Meritxell Huch,Anna M Dowbaj,Richard Butler

doi:10.1016/j.stem.2021.07.002

Abstract

SummaryIn the liver, ductal cells rarely proliferate during homeostasis but do so transiently after tissue injury. These cells can be expanded as organoids that recapitulate several of the cell-autonomous mechanisms of regeneration but lack the stromal interactions of the native tissue. Here, using organoid co-cultures that recapitulate the ductal-to-mesenchymal cell architecture of the portal tract, we demonstrate that a subpopulation of mouse periportal mesenchymal cells exerts dual control on proliferation of the epithelium. Ductal cell proliferation is either induced and sustained or, conversely, completely abolished, depending on the number of direct mesenchymal cell contacts, through a mechanism mediated, at least in part, by Notch signaling. Our findings expand the concept of the cellular niche in epithelial tissues, whereby not only soluble factors but also cell-cell contacts are the key regulatory cues involved in the control of cellular behaviors, suggesting a critical role for cell-cell contacts during regeneration.

Highlights

The adult liver epithelium comprises hepatocytes and biliary ducts lined by liver ductal cells (DCs, known as cholangiocytes)
We first sought to characterize the proximate neighbors of the ductal epithelium, which we hypothesized could act as a regulatory niche for DC-driven regeneration
We found that the hematopoietic and cancer stem cell and surface marker SCA1 labeled cells exclusively localized at the PT, in proximity to and including the biliary ductal epithelium, as identified by osteopontin (OPN)

Summary

Introduction

The adult liver epithelium comprises hepatocytes and biliary ducts lined by liver ductal cells (DCs, known as cholangiocytes). Healthy adult DCs can be expanded in vitro as self-renewing liver organoids in a 3D extracellular matrix (Matrigel) and a defined cocktail of growth factors (R-Spondin-1 [RSPO1], Fibroblast Growth Factor 10 [FGF10], epidermal growth factor [EGF], and Hepatocyte Growth Factor [HGF]; Huch et al, 2013, 2015) that recapitulate the transient mitogenic milieu of the regenerating liver (Apte et al, 2008). Using this model system, we have shown that liver ductal organoids recapitulate many aspects of liver regeneration in a dish (Aloia et al, 2019). The contribution of the latter in the ductal-mediated regeneration of the liver are largely unknown

Results

Discussion

Conclusion