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Description
Title: | Engineered microenvironments for studying liver progenitor differentiation |
Author(s): | Kaylan, Kerim Berk |
Advisor(s): | Underhill, Gregory H. |
Department / Program: | Bioengineering |
Discipline: | Bioengineering |
Degree Granting Institution: | University of Illinois at Urbana-Champaign |
Degree: | M.S. |
Genre: | Thesis |
Subject(s): | liver progenitors
bipotential liver progenitors hepatoblasts hepatocytes cholangiocytes bile duct cells liver progenitor differentiation osteopontin Opn Spp1 albumin Alb morphogenesis tissue morphogenesis bile duct morphogenesis bile duct formation liver development Notch Notch signaling Jagged-1 Jag1 Delta-like 1 Dll1 Delta-like 4 Dll4 transforming growth factor β TGFβ TGFβ signaling TGFβ1 Extracellular matrix proteins (ECM) collagen I collagen III collagen IV laminin fibronectin co-cultures Green fluorescent protein (GFP) microenvironment microenvironmental regulation cell microenvironment cellular microenvironment cell microarrays cellular microarrays engineered microenvironments |
Abstract: | The bipotential differentiation of liver progenitor cells underlies liver development and bile duct formation as well as liver regeneration and disease. Both TGFβ and Notch signaling are known to play important roles in the liver progenitor specification process and subsequent 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 to induce 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. |
Issue Date: | 2016-03-29 |
Type: | Text |
URI: | http://hdl.handle.net/2142/90492 |
Rights Information: | © 2016 Kerim B. Kaylan |
Date Available in IDEALS: | 2016-07-07 |
Date Deposited: | 2016-05 |
This item appears in the following Collection(s)
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Graduate Dissertations and Theses at Illinois
Graduate Theses and Dissertations at Illinois