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

Funding Type: 
SEED Grant
Grant Number: 
RS1-00409
ICOC Funds Committed: 
$0
Disease Focus: 
Multiple Sclerosis
Neurological Disorders
Immune Disease
Stem Cell Use: 
Embryonic Stem Cell
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.
Progress Report: 
  • Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that results in demyelination and axonal loss, culminating in extensive disability through defects in neurologic function. The demyelination that defines MS pathology is progressive over time; however, studies indicate that myelin repair can occur during the course of disease in patients with MS and in animal models designed to mimic the immunopathogenesis of MS. While it is generally thought that endogenous oligodendrocyte precursor cells (OPCs) are largely responsible for spontaneous remyelination, it is unclear why these cells are only able to transiently induce myelin repair in the presence of ongoing disease. Along these lines, two therapies for demyelinating diseases look promising; implanting OPCs into sites of neuroinflammation that are directly capable of inducing remyelination of the damaged axons and/or modifying the local environment to stimulate and support remyelination by endogenous OPCs. Indeed, we have shown that human embryonic stem cell (hESC)-derived oligodendrocytes surgically implanted into the spinal cords of mice with virally induced demyelination promoted focal remyelination and axonal sparing. We are currently investigating how the implanted OPCs positionally migrate to areas of on-going demyelination and the role these cells play in repairing the damaged CNS. The purpose of this research is to identify the underlying mechanism(s) responsible for hESC-induced remyelination.
  • Oligodendrocyte progenitor cells (OPCs) are important in mediating remyelination in response to demyelinating lesions. As such, OPCs represent an attractive cell population for use in cell replacement therapies to promote remyelination for treatment of human demyelinating diseases. High-purity OPCs have been generated from hESC and have been shown to initiate remyelination associated with improved motor skills in animal models of demyelination. We have previously determined that engraftment of hESC-derived OPCs into mice with established demyelination does not significantly improve clinical recovery nor reduce the severity of demyelination. Importantly, remyelination is limited following OPC transplantation. These findings highlight that the microenvironment is critical with regards to the remyelination potential of engrafted cells. In addition, we have determined that human OPCs are capable of migrating in response to proinflammatory molecules often associated with human neuroinflammatory diseases such as multiple sclerosis. This is an important observation in that it will likely be necessary for engrafted OPCs to be able to positionally navigate within tissue in order to move from the site of surgical transplantation to areas of damage to initiate repair and tissue remodeling. Finally, we have also made a novel discovery of a unique signaling pathway that protects OPCs from damage/death in response to treatment with proinflammatory cytokines. We believe this is an important and translationally relevant observation as OPCs are critical in contributing to remyelination and remyelination failure is an important clinical feature for many human demyelinating diseases inclusing spinal cord injury and MS. We have identified a putative protective ligand/receptor interaction affords protection from cytokine-induced apoptosis. These findings may reveal novel avenues for therapeutic intervention to prevent damage/death of OPCs and enhance remyelination.

© 2013 California Institute for Regenerative Medicine