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Title:Engineered microenvironments for studying liver progenitor differentiation
Author(s):Kaylan, Kerim Berk
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:Thesis
URI:http://hdl.handle.net/2142/90492
Rights Information:© 2016 Kerim B. Kaylan
Date Available in IDEALS:2016-07-07
Date Deposited:2016-05


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