Liver transplantation is the second most common form of solid organ transplant with more than a quarter of listed patients expiring prior to receiving an organ. Developing a means to either stimulate liver regeneration or cultivate liver cells under tissue culture conditions could potentially abrogate the need for transplantation. While several groups have attempted to cultivate liver stem cells in the laboratory, robust conditions that could fulfill the current transplantation needs have yet to be developed. Our laboratory has made two recent discoveries that may be useful for the expansion of liver stem cells. First, we have found that changes in Hippo signaling can reprogram mature hepatocytes into cells displaying characteristics of bipotential liver progenitor cells. Hippo signaling has ben previously described as a potent growth regulator, but this finding suggests this pathway also confers increased plasticity upon differentiated cells. Secondly, we have developed culture conditions in which manipulation of Hippo signaling allows for long-term growth and enormous expansion of liver progenitors and reprogrammed hepatocytes. We propose to investigate the nature of these findings in three parts: 1) Utilize a novel Hippo reporter mouse line to determine whether endogenous Hippo activity can mark the elusive liver progenitor cell in situ. 2) Elucidate whether reprogrammed-hepatocytes contain bona fide stem cells as tested functionally in vitro and in vivo;and 3) Investigate the downstream mechanisms by which YAP reprograms hepatocytes. Completion of this project would elucidate the nature of the liver progenitor/stem cell compartment;and explore the plasticity of liver cell fate as a strategy to develop transplantable cells for transplantation.

Public Health Relevance

The barrier that normal tissues encounter when they have reached the correct size is likely to impact on the very early stages of tumorigenesis. Here we propose to elucidate how a pathway that regulates organ size in mammal's controls stem cells, a more complete understanding of how activity of this pathway is controlled during development may highlight suitable cell replacement therapeutic strategies for liver diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK099559-01
Application #
8562366
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Serrano, Jose
Project Start
2013-07-01
Project End
2018-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$380,625
Indirect Cost
$163,125
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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Yimlamai, Dean; Christodoulou, Constantina; Galli, Giorgio G et al. (2014) Hippo pathway activity influences liver cell fate. Cell 157:1324-38
Tremblay, Annie M; Missiaglia, Edoardo; Galli, Giorgio G et al. (2014) The Hippo transducer YAP1 transforms activated satellite cells and is a potent effector of embryonal rhabdomyosarcoma formation. Cancer Cell 26:273-87
Halder, Georg; Camargo, Fernando D (2013) The hippo tumor suppressor network: from organ size control to stem cells and cancer. Cancer Res 73:6389-92