Abstract
Dynamic remodeling of the intrahepatic biliary epithelial tissue plays key roles in liver regeneration, yet the cellular basis for this process remains unclear. We took an unbiased approach based on in vivo clonal labeling and tracking of biliary epithelial cells in the three-dimensional landscape, in combination with mathematical simulation, to understand their mode of proliferation in a mouse liver injury model where the nascent biliary structure formed in a tissue-intrinsic manner. An apparent heterogeneity among biliary epithelial cells was observed: whereas most of the responders that entered the cell cycle upon injury exhibited a limited and tapering growth potential, a select population continued to proliferate, making a major contribution in sustaining the biliary expansion. Our study has highlighted a unique mode of epithelial tissue dynamics, which depends not on a hierarchical system driven by fixated stem cells, but rather, on a stochastically maintained progenitor population with persistent proliferative activity.
Highlights
Tissue growth, maintenance, and remodeling play central roles in ensuring the structural and functional integrity of adult organs and are achieved through the coordinated actions of cell proliferation and differentiation
Prom1, better known as the surface antigen CD133, has been reported to be an ’oval cell/liver progenitor cell (LPC) marker’ in injured liver (Rountree et al, 2007; Dorrell et al, 2011), but it is expressed in biliary epithelial cells (BECs) under normal conditions (Suzuki et al, 2008)
X-gal staining experiments using liver sections showed that nuclear localization signal-conjugated LacZ (nLacZ) was expressed in a BEC-specific manner (Figure 1c, left and right panels)
Summary
Maintenance, and remodeling play central roles in ensuring the structural and functional integrity of adult organs and are achieved through the coordinated actions of cell proliferation and differentiation. In these processes, the location, arrangement and timing of cell proliferation are tightly regulated in tissue-specific and context-dependent manners (Barker et al, 2010). These cells are maintained in a quiescent state in which they stable epithelial sheets and tubules They enter dynamic regeneration processes once the organ suffers tissue loss or various types of injury.
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