University of Illinois Urbana-Champaign

Engineered microenvironments for studying liver progenitor differentiation

Kaylan, Kerim Berk

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https://hdl.handle.net/2142/90492

Description

Title
Engineered microenvironments for studying liver progenitor differentiation
Author(s)
Kaylan, Kerim Berk
Issue Date
2016-03-29
Director of Research (if dissertation) or Advisor (if thesis)
Underhill, Gregory H.
Department of Study
Bioengineering
Discipline
Bioengineering
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
M.S.
Degree Level
Thesis
Keyword(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.
Graduation Semester
2016-05
Type of Resource
text
Permalink
http://hdl.handle.net/2142/90492
Copyright and License Information
© 2016 Kerim B. Kaylan

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