Abstract
The bipotential differentiation of liver progenitor cells underlies liver development and bile duct formation as well as liver regeneration and disease. TGFβ and Notch signaling are known to play important roles in the liver progenitor specification process and tissue morphogenesis. However, the complexity of these signaling pathways and their currently undefined interactions with other microenvironmental factors, including extracellular matrix (ECM), remain barriers to complete mechanistic understanding. Utilizing a series of strategies, including co-cultures and cellular microarrays, we identified distinct contributions of different Notch ligands and ECM proteins in the fate decisions of bipotential mouse embryonic liver (BMEL) progenitor cells. In particular, we demonstrated a cooperative influence of Jagged-1 and TGFβ1 on cholangiocytic differentiation. We established ECM-specific effects using cellular microarrays consisting of 32 distinct combinations of collagen I, collagen III, collagen IV, fibronectin, and laminin. In addition, we demonstrated that exogenous Jagged-1, Delta-like 1, and Delta-like 4 within the cellular microarray format was sufficient for enhancing cholangiocytic differentiation. Further, by combining Notch ligand microarrays with shRNA-based knockdown of Notch ligands, we systematically examined the effects of both cell-extrinsic and cell-intrinsic ligand. Our results highlight the importance of divergent Notch ligand function and combinatorial microenvironmental regulation in liver progenitor fate specification.
Highlights
The bipotential differentiation of liver progenitor cells underlies liver development and bile duct formation as well as liver regeneration and disease
The importance of Notch in bile duct morphogenesis is further highlighted by Alagille syndrome, an autosomal dominant genetic disorder caused by mutations in NOTCH2 or JAG1 and associated with paucity of intrahepatic bile ducts, neonatal jaundice, cholestasis, and other abnormalities[11,12,13,14]
We demonstrate a cooperative role of Notch and TGFβ in liver progenitor fate specification, including unique effects of the Notch ligands Jag[1] and Dll[1] on the differentiation process
Summary
The bipotential differentiation of liver progenitor cells underlies liver development and bile duct formation as well as liver regeneration and disease. Progenitor cell differentiation and bile duct morphogenesis are driven by spatially-dependent and temporally-sequenced cell–cell and cell–factor interactions coordinated by several signaling pathways, namely Notch and TGFβ 1–4. Despite many insights gained into the pathways involved in liver progenitor specification, the complete mechanistic details of the link between liver progenitor cell fate/function and liver duct morphogenesis as well as the combined impact of feedback between Notch, TGFβ , and ECM proteins remain unclear. We exploited a cellular microarray platform, which exhibits well-defined material properties and unique capabilities for simultaneously examining multiple types of microenvironmental regulation[34,35,36] Using this approach, we investigated liver progenitor differentiation within defined microenvironments consisting of systematically introduced soluble factors, ECM components, and cell–cell signaling ligands
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