Abstract
The progenitor cells of the developing liver can differentiate toward both hepatocyte and biliary cell fates. In addition to the established roles of TGFβ and Notch signaling in this fate specification process, there is increasing evidence that liver progenitors are sensitive to mechanical cues. Here, we utilized microarrayed patterns to provide a controlled biochemical and biomechanical microenvironment for mouse liver progenitor cell differentiation. In these defined circular geometries, we observed biliary differentiation at the periphery and hepatocytic differentiation in the center. Parallel measurements obtained by traction force microscopy showed substantial stresses at the periphery, coincident with maximal biliary differentiation. We investigated the impact of downstream signaling, showing that peripheral biliary differentiation is dependent not only on Notch and TGFβ but also E-cadherin, myosin-mediated cell contractility, and ERK. We have therefore identified distinct combinations of microenvironmental cues which guide fate specification of mouse liver progenitors toward both hepatocyte and biliary fates.
Highlights
The cells which populate the hepatic diverticulum during development and later serve as the source of liver parenchyma are termed bipotential progenitor cells, or hepatoblasts, as they are capable of differentiating toward both hepatocytic and biliary epithelial cell fates
Using combinatorial extracellular matrix (ECM) protein arrays, we showed that TGFb-induced biliary differentiation of liver progenitor cells is coordinated by both substrate stiffness and matrix
Bipotential mouse embryonic liver (BMEL) progenitor cells, which are capable of assuming a hepatocytic or biliary fate (Strick-Marchand and Weiss, 2002), were seeded on these Notch ligand arrays and cultured under differentiation conditions for t 1⁄4 72 h, at which point we immunolabeled for OPN and the hepatocytic marker albumin (ALB)
Summary
The cells which populate the hepatic diverticulum during development and later serve as the source of liver parenchyma are termed bipotential progenitor cells, or hepatoblasts, as they are capable of differentiating toward both hepatocytic and biliary epithelial cell fates. While differentiation of liver progenitors toward a hepatocytic fate is guided by signaling through Wnt, HGF, and FGF (Micsenyi et al, 2004; Berg et al, 2007; Schmidt et al, 1995), biliary fate is regulated by Notch and TGFb signaling (Kodama et al, 2004; Clotman et al, 2005; Zong et al, 2009). The progenitor cells of the developing liver integrate a diverse set of biochemical cues during fate specification. Using combinatorial extracellular matrix (ECM) protein arrays, we showed that TGFb-induced biliary differentiation of liver progenitor cells is coordinated by both substrate stiffness and matrix
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