Liver disease affects millions of people worldwide. Hepatocyte transplantation is considered a potential treatment for liver diseases and a bridge for patients awaiting liver transplantation, but its application has been hampered by a limited supply of hepatocytes. The capacity of embryonic stem (ES) cells to form multiple differentiated cell types in culture provides a unique model system for the generation of transplantable lineages and tissues for cell replacement therapies. The long-term goal of this project is to define the mechanisms regulating the specification of ES cell-derived endoderm to a hepatic fate, and maturation to functional hepatocytes that are able to repopulate a diseased liver. We will test the hypothesis that endothelial cells support ES cell-derived endoderm cell survival, growth, hepatic specification and maturation during liver development and we will subsequently determine the mechanisms underlying these cell-cell interactions. Similar to what occurs during normal liver development, liver transplant repopulation requires highly orchestrated cell-cell interactions. We will identify the important molecular players in the crosstalk between endothelial cells and hepatic cells that could be relevant for promoting liver regeneration following transplantation with ES cell-derived hepatic cells. The characterization of these cell-cell interactions will provide a unique model for basic studies on the establishment of the hepatic lineage as well as provide functional hepatic cell for transplantation in pre-clinical models of liver cell replacement therapy.

Public Health Relevance

Hepatocyte transplantation is considered a potential but unrealized treatment for liver diseases. Hepatocytes generated from embryonic stem (ES) cell cultures could provide an unlimited supply of such cells for transplantation. We will test the hypothesis that interactions between endothelial cells and ES cell-derived hepatic cells during transplantation promote successful liver regeneration. The characterization of these cell- cell interactions will provide insight into the establishment of the hepatic lineage from ES cell cultures, as well as provide functional ES cell-derived hepatic cells for pre-clinical models of liver cell replacement therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK087867-03
Application #
8250462
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Serrano, Jose
Project Start
2010-04-20
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
3
Fiscal Year
2012
Total Cost
$348,195
Indirect Cost
$142,770
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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Han, Songyan; Goldman, Orit; Gouon-Evans, Valerie (2014) Liver progenitor cell and KDR. Cell Cycle 13:1051-2
Gouon-Evans, Valerie (2014) The race for regeneration: Pluripotent-stem-cell-derived 3D kidney structures. Cell Stem Cell 14:5-6
Sourisseau, Marion; Goldman, Orit; He, Wenqian et al. (2013) Hepatic cells derived from induced pluripotent stem cells of pigtail macaques support hepatitis C virus infection. Gastroenterology 145:966-969.e7
Goldman, Orit; Han, Songyan; Sourrisseau, Marion et al. (2013) KDR identifies a conserved human and murine hepatic progenitor and instructs early liver development. Cell Stem Cell 12:748-60
Han, Songyan; Dziedzic, Noelle; Gadue, Paul et al. (2011) An endothelial cell niche induces hepatic specification through dual repression of Wnt and Notch signaling. Stem Cells 29:217-28