Stability of liver-specific functions in hepatocytes is critical to the success of hepatocyte-based therapies for liver disease. The limitations in our current understanding of relevant hepatocellular cues are, in part, due to the structural complexity of the liver microarchitecture- repeating units with zones of hepatocyte specialization, gradients of soluble factors, interactions with extracellular matrix and non-parenchymal cells in 3-dimensions, and so on. The importance of each of these structural features on liver function has been widely emphasized;however, because it has historically been difficult to modulate these cues independently from each other, it remains unclear how they cooperate to exert their influence on hepatocellular function. The investigator has previously used micropatterning techniques to show that the balance between homotypic and heterotypic cell-cell interactions is a critical feature of tissue microarchitecture that dictates liver-specific function. It has now become evident that other factors in the microenvironment conspire to modulate the phenotype of hepatocytes including: oxygen concentration, growth factors, extracellular matrix, and 2- versus 3-dimensionality. The working hypothesis underlying the present proposal is that tissue microarchitecture influences zonal hepatocyte function through the interplay of soluble cues (O2, growth factors) and adhesive cues (cells, ECM) in the hepatocyte microenvironment. The general goal of this RENEWAL proposal is therefore to relate tissue microarchitecture to hepatocyte function by identifying and characterizing the mechanisms by which acellular cues in the local microenvironment cooperate to modulate hepatocyte function. Towards this end, the specific aims of this proposal are: (1) To investigate the cooperation of soluble factors (O2, growth factors, and paracrine signals) in regulating zonal hepatocyte function, (2) To investigate the cooperation of adhesive factors (ECM, cells) and soluble factors in regulating zonal function, and (3) To examine the role of soluble and adhesive factors in regulating zonal hepatocyte responses in 3-D microenvironments. In order to accomplish these goals, the investigator has established a research program where modern biological tools are integrated with several enabling technological platforms. A clear picture of the interplay between soluble and adhesive cues in 2- and 3-dimensions will be fundamental to the future design and implementation of hepatocyte-based therapies to treat liver disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK056966-09
Application #
8019014
Study Section
Special Emphasis Panel (ZRG1-CB-N (10))
Program Officer
Serrano, Jose
Project Start
2000-09-30
Project End
2012-02-29
Budget Start
2010-12-01
Budget End
2012-02-29
Support Year
9
Fiscal Year
2011
Total Cost
$328,114
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Type
Organized Research Units
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Shan, Jing; Schwartz, Robert E; Ross, Nathan T et al. (2013) Identification of small molecules for human hepatocyte expansion and iPS differentiation. Nat Chem Biol 9:514-20
Stevens, K R; Ungrin, M D; Schwartz, R E et al. (2013) InVERT molding for scalable control of tissue microarchitecture. Nat Commun 4:1847
Underhill, Gregory H; Galie, Peter; Chen, Christopher S et al. (2012) Bioengineering methods for analysis of cells in vitro. Annu Rev Cell Dev Biol 28:385-410
Li, Cheri Y; Wood, David K; Hsu, Caroline M et al. (2011) DNA-templated assembly of droplet-derived PEG microtissues. Lab Chip 11:2967-75
Chen, Alice A; Thomas, David K; Ong, Luvena L et al. (2011) Humanized mice with ectopic artificial liver tissues. Proc Natl Acad Sci U S A 108:11842-7
Jones, Christopher T; Catanese, Maria Teresa; Law, Lok Man J et al. (2010) Real-time imaging of hepatitis C virus infection using a fluorescent cell-based reporter system. Nat Biotechnol 28:167-71
Chen, Alice A; Underhill, Gregory H; Bhatia, Sangeeta N (2010) Multiplexed, high-throughput analysis of 3D microtissue suspensions. Integr Biol (Camb) 2:517-27
Ploss, Alexander; Khetani, Salman R; Jones, Christopher T et al. (2010) Persistent hepatitis C virus infection in microscale primary human hepatocyte cultures. Proc Natl Acad Sci U S A 107:3141-5
Chen, Alice A; Khetani, Salman R; Lee, Sunyoung et al. (2009) Modulation of hepatocyte phenotype in vitro via chemomechanical tuning of polyelectrolyte multilayers. Biomaterials 30:1113-20
March, Sandra; Hui, Elliot E; Underhill, Gregory H et al. (2009) Microenvironmental regulation of the sinusoidal endothelial cell phenotype in vitro. Hepatology 50:920-8

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