The function of YAP in human embryonic stem cells

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Grant Award Details

Grant Type:

Basic Biology II

Grant Number:

RB2-01547

Investigator(s):

Name:

Dr. Kun-Liang Guan

Institution:

University of California, San Diego

Type:

Human Stem Cell Use:

Embryonic Stem Cell, iPS Cell

Cell Line Generation:

Embryonic Stem Cell, iPS Cell

Award Value:

$1,245,693

Status:

Closed

Progress Reports

Reporting Period:

Year 1

Reporting Period:

Year 2

Reporting Period:

Year 3

The Hippo tumor suppressor pathway was initially identified in the fruit fly to control tissue growth and organ size. Subsequent studies show that this pathway is highly conserved and also controls organ size in mammals. Hippo pathway controls organ size by regulating cell numbers. YAP and TAZ are two transcription factors that are inhibited by the Hippo pathway. Inhibition of YAP/TAZ represents the major functional output of the Hippo signaling. YAP and TAZ function to promote cell growth and organ size by promoting stem cell growth. Furthermore, mutation leading to dysregulation of the Hippo pathway is associated with cancer development. In fact, high YAP activity is frequently found in human cancer. Furthermore, TAZ has been shown to play important role in breast cancer stem cells. We have been investigating the mechanism of the Hippo pathway regulation and its role in stemness, differentiation, and tumorigenesis. We discovered the cell-cell contact and cell-matrix interaction play critical role in Hippo pathway regulation. In other words, the Hippo pathway can sense its neighbors and environment, and then relays these signals to tell the cell whether to proliferate, survive, or die. These functions are important for maintenance of both embryonic stem cells and tissue specific progenitor cells. Furthermore, we have identified hormones that act through G-protein coupled receptor to modulate the Hippo-YAP activity. These results suggest possible physiological cues that may regulate YAP activity to control tissue stem cells, therefore to influence organ size and tissue regeneration. Finally, we have isolated and characterized inhibitors that can modulate the Hippo pathway. These inhibitors are useful reagents for research and potential anti-cancer drugs. Importantly, our study shows that some of the FDA approved drugs can potently inhibits YAP. These novel findings gain new insights into the Hippo pathway regulation and provide valuable scientific knowledge of targeting the Hippo pathway for therapeutic intervention.

Grant Application Details

Application Title:

The function of YAP in human embryonic stem cells

Public Abstract:

Embryonic stem cells have the potential to generate all tissue types that could be used for regenerative medicine, such as replacement of damaged neurons, replenish of insulin secreting beta cells, or generation of blood cells. The discovery of in vitro reprogramming of somatic cells (normal cells in our body) into induced pluripotent stem cells (iPS, which has the potential to differentiate into many different cell types) offers an exciting reality that patient specific pluripotent stem cells could be obtained. Cells derived from patient specific iPS cells would less likely to cause immune rejection when transplanted back into the patient. The rapid progresses in stem cell research make regenerative medicine from scientific fiction close to medical reality. However, many key issues, such as the efficiency of iPS induction and efficiency of stem cell differentiation in vitro (outside of our body), remain to be resolved before stem cell therapy becomes a routine medical practice.

YAP is a transcription co-activator, which can help certain transcription factors to stimulate gene expression. Previous studies have shown that elevated YAP activity makes organ bigger. For example, YAP overexpression in mouse livers increases liver size by 4-5 fold. High YAP activity has also been observed in some human caners. We have found that YAP has an important role in mouse embryonic stem cells. Decreased YAP activity forces stem cell to differentiate while high YAP activity maintains stem cell properties even under differentiation conditions. We also found that in mouse embryonic stem cells YAP stimulates expression of many genes known to be important for stem cell pluripotency. In this project, we will study the function of YAP in human embryonic stem cells. We hope to understand how YAP promotes the stem cell properties. In addition, we would like to know how YAP itself is regulated in the human embryonic stem cells, by specifically determining YAP protein levels, localization in the cell, and degradation. Finally, we will isolate YAP activators and inhibitors. YAP activators may help us more efficiently generating iPS cells from somatic human cells. Conversely, YAP inhibitors may facilitate in vitro differentiation of human embryonic stem cells, therefore reduce the risk of teratoma formation caused by residual undifferentiated ESC in stem cell therapy. Completion of this project will help us to understand the basic biology of stem cells and may provide candidates for future drug development.

Statement of Benefit to California:

Stem cell therapy has the potential to revolutionize the treatment of many common diseases that afflict residents of the State of California. Alzheimer’s disease, diabetes, heart failure, anemia and arthritis are just a few of the illnesses that could potentially be treated. The benefits of the proposed research to the State of California and to its residents will be multiple. It will accelerate the pace of stem cell research, by discovering the novel function of YAP in human embryonic stem cells. The function of YAP in embryonic stem cells has not been reported while our preliminary study strongly indicates a success of this project. Our study will provide scientific knowledge of ESC stemness maintenance and research tools to more efficiently reprogramming iPS from normal somatic human cells. This would facilitate generation of patient-derived iPS cells. Moreover, as we hypothesized, inhibition of YAP activity will deplete human embryonic stem cells in in vitro differentiation; therefore decrease the risk of tumor formation in receipt patients. This project will generate knowledge beneficial to stem cell therapy and provide drug candidates for regenerative medicine in the state of California.

Publications

Nat Cell Biol (2011): The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. (PubMed: 21808241)
Cell (2012): Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. (PubMed: 22863277)