The role of HER2 signaling in differentiation and maintenance of human embryonic stem cells

Funding Type: 
SEED Grant
Grant Number: 
RS1-00411
Investigator: 
ICOC Funds Committed: 
$0
Public Abstract: 
The ability to propagate high quality human embryonic stem cells (hESCs) that are capable of giving rise to multiple cell types is essential in using hESCs to treat human diseases. Understanding the signaling pathways that control the maintenance of pluripotency and differentiation of hESCs is necessary for endowing such ability. The goal of this project is to determine whether HER2, a receptor tyrosine kinase, is essential in maintaining hESCs. HER2 is a multiple functional protein. De-regulation of HER2 expression or signaling is implicated in several human diseases. For example, over-expression of HER2 is found in 20-30% of breast cancer patients. Herceptin, a humanlized blocking monoclonal antibody, has been approved by the Food and Drug Agency to treat breast cancer patients. HER2 is required as an essential partner for the response of cells to multiple growth factors, including neuregulin (NRG). Mutation of the NRG1 gene is associated with Schizophrenia in several populations. Studies in mice suggest that HER2 may play a role in the etiology of Hirschsprung disease and in preventing dilated cardiomyopathy and muscular dystrophy. Interestingly, some breast cancer patients treated with Herceptin develop cardiac dysfunction, revealing multiple functions of HER2 and the complication of designing an ideal therapy. NRG1 has been shown to play a role in the formation of the conduction system (pacemaker) of the heart in mice. Improper processing of NRG1 may play a role in Alzheimer's Disease and neuropathy. We found that NRG1 plays a role in the recovery rate of rat neural stem cells. HER2 is highly expressed in undifferentiated hESCs. These data demonstrate that HER2 has pleitropic effects on multiple cell types and organs and suggest that HER2 is capable of integrating diverse signaling pathways that are essential in the control of maintenance and/or differentiation of hESCs where HER2 is highly expressed. Understanding whether and how HER2 regulates the maintenance and/or differentiation of hESCs may provide insight into harnessing the strategy to grow and use hESCs to treat human disease.
Statement of Benefit to California: 
The ability to propagate high quality human embryonic stem cells (hESCs) that are capable of giving rise to multiple cell types is essential in using hESCs to treat human diseases. Understanding the signaling pathways that control the maintenance of pluripotency and differentiation of hESCs is necessary for endowing such ability. HER2 is a receptor tyrosine kinase and has been shown to play essential roles or is implicated in breast cancer, dilated cardiomyopathy, muscular dystrophy, heart pace maker, peripheral neuropathy, Schizophrenia and Alzheimer's Disease. For example, over-expression of HER2 is found in 20-30% of breast cancer patients. Herceptin, a humanlized blocking monoclonal antibody, has been approved by the Food and Drug Agency to treat breast cancer patients. Several lines of evidence suggest that HER2 is a multiple functional protein and may play essential roles in the maintenance and/or differentiation of hESCs. Understanding whether and how HER2 regulates the maintenance and differentiation of hESCs may provide insight into harnessing the strategy to grow and use high quality hESCs to treat human disease.

© 2013 California Institute for Regenerative Medicine