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http://icahn.mssm.edu/departments-and-institutes/developmental-and-regenerative-biology
 

Gouon-Evans Lab - Research

    The Gouon-Evans laboratory aims to understand liver development by studying this process in mouse embryos mouse and human pluripotent stem cells (PSC) as well as human specimens. Additionally, we are investigating the ultimate utility of human PSC-derived hepatic cells in cell therapy for liver diseases.

Liver development

    Liver development is a paradigm for understanding the complex problems navigated by undifferentiated cells, as they become mature organs. The work of my lab has redefined our perception of liver development, as we have uncovered a heterogeneity and plasticity in the progenitors that give rise to hepatic and endothelial cells that form the liver. Moreover, I am driven by the goal to comprehend mammalian liver development so as to inform protocols to generate functional hepatic cells from pluripotent stem cells (PSC) to ultimately use these cells in cell therapy to repair diseased livers. This is an unmet and urgent need as abundant, mature and functional PSC-derived hepatic cells would overcome the scarcity of liver donors for transplantation, which is the current but insufficient treatment for the many patients suffering from end-stage liver disease. Although a growing literature has established efficient protocols to generate hepatic cells in vitro, the PSC-derived hepatic cells remain inefficient at repopulating diseased liver.

    Hepatic cells derived from PSC cultures need a niche to develop and mature properly, reflecting the environment under which hepatocytes develop in the embryo. We demonstrated that endothelial cells are one of the cell components of the hepatic niche that induces hepatic specification of endoderm and subsequent maturation (Han et al., Stem Cells, 2011). Within the hepatic cell niche, we have identified a hepatic progenitor cell that unexpectedly expresses the VEGF receptor 2 (also called KDR), which has traditionally been thought to be a marker of mesoderm derivatives. This surprising finding was validated in fetal and adult liver in lineage tracing mouse models (Figure 1) and in the human embryonic stem cells (ESC) system (Goldman et al., Cell Stem Cell, 2013). The KDR-expressing endoderm cell is a true progenitor for hepatic cells, as it can differentiate further to a mature hepatic cell displaying unique properties of hepatocytes, for example the capacity to be infected by the hepatitis C virus (HCV). While this finding differs from the commonly held assumption that there are unique germline markers, we believe it demonstrates that this classical mesoderm marker is indeed expressed in cells, which form the liver, an endoderm organ. 



    We have translated these findings to the pigtail macaque (Macaca nemestrina) induced-PSC (iPSC) system to generate hepatic cells that support the entire HCV life cycle by modulating the HCV entry process (Sourisseau et al, Gastroenterology, 2013). This work introduced the primate pigtail macaque as a suitable and clinically relevant HCV in vivo model system. On going preliminary data indicate that human ESC-derived hepatic cells can also be infected with hepatitis B virus (HBV) and therefore could provide an unprecedented cell culture system to study HBV life cycle.

   We recently discovered that these unique KDR+ progenitors are bi-potential cells that differentiate not only into hepatic cells (Goldman et al., Cell Stem Cell, 2013) but also into functional endothelial cells (Goldman et al., Stem Cell Reports, 2014) (Figure 2). These bi-potential progenitors were identified in the developing liver using endoderm lineage tracing mouse models. This study introduced the concept that endothelial cells originate not exclusively from mesoderm but also from endoderm during liver organogenesis.

Cell Therapy for liver disease

    Liver transplantation is currently the only treatment for acute and chronic liver failure. Hepatocyte transplantation is considered an alternative treatment and a bridge for patients awaiting liver transplantation, but its application has been hampered by a limited supply of hepatocytes. Hepatocytes derived from human pluripotent stem cells (hPSCs) including embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) could provide an unlimited supply for cell therapy. However, generation of functional hepatic cells is still a challenge.

    We are currently using an acute and a chronic mouse model with liver deficiency. The chronic model of liver disease is triggered by the deficiency of FAH expression and the acute injury is induced by a single injection of the hepatotoxic carbon tetrachloride CCl4. We hope by modulating genetically or pharmacologically the transplanted PSC-derived hepatic cells to treat liver injuries.



 
lab info



Valerie Gouon-Evans, ASSISTANT PROFESSOR
valerie.gouon-evans@mssm.edu

212-241-4033 (office)
212-241-8191 (lab)
646-537-9695 (fax)

lab members:
Orit Goldman
Wissam Hamou
Songyan Han

see photos and more here.
mailto:valerie.gouon-evans@mssm.edu?subject=gouonevanslab.htmlgouonevanslab.htmlgouonevanslab.htmlgouonevanslab.htmlshapeimage_15_link_0shapeimage_15_link_1shapeimage_15_link_2shapeimage_15_link_3shapeimage_15_link_4
key publications

2014
Goldman O*, Han S*, Gouon-Evans V.,
Liver progenitor cell and KDR.
Cell Cycle, 13,7:1051-1052.
Goldman, O.*, S. Han*, W. Hamou, V. Jodon de Villeroche, G. Uzan, H. Lickert, V. Gouon-Evans,
Endoderm generates endothelial cells during liver development. 
Stem Cell Reports, 3, 556-565.

2013
Goldman, O.*, S. Han*, M. Sourrisseau, N. Dziedzic, W. Hamou, B. Corneo, S. D'Souza, T. Sato, D.N. Kotton, K.D. Bissig, T. Kalir, A. Jacobs, T. Evans, M.J. Evans, and V. Gouon-Evans.,
KDR Identifies a Conserved Human and Murine Hepatic Progenitor and Instructs Early Liver Development.
Cell Stem Cell, 12:748-760. PMID: 23746980.

Marion Sourisseau, M.*, Goldman, O.*, He, W., Gori, J. L., Kiem, H., Gouon-Evans, V.,** Evans, M.J.**,
K Pigtail macaque induced pluripotent stem cell-derived hepatocytes support hepatitis C virus infection.
Gastroenterology, 145:5,966-969 e7.

2012
Han, S., Bourdon, A., Hamou, W., Dziedzic, N., Goldman, O., and Gouon-Evans, V.,
Generation of functional hepatic cells from pluripotent stem cells.
ournal of Stem Cell Research & Therapy, J S10-008.

2011
Han, S., Dziedzic, N., Gadue, P., Keller, G., Gouon-Evans V.,
An endothelial cell niche induces hepatic specification through dual repression of Wnt and Notch Signaling.,  
Stem Cells, 29, 217-28.

Green, M., Chen, A., Nostro, MC, d’Souza, S., Schaniel, C., Lemischka, I.R., Gouon-Evans, V., Keller, G., Snoeck, H.,
Generation of anterior foregut endoderm from human embryonic and induced pluripotent stem cells.
Nat Biotechnol, 29, 267-72. 

Christodoulou C, Longmire T, Shen S, Bourdon A, Sommer  C, Gadue P,  Spira A, Gouon-Evans V, Murphy G, Mostoslavsky G, and Kotton D.,
Induced pluripotent stem cells and embryonic stem cells display similar capacity to form definitive endoderm despite molecular differences in imprinted genes.
J Clin Invest., 121, 2313-25. 

Authors contributed equally, ** co-corresponding authors.

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