MHC-I suppression for long-term survival of hESC-derived oligodendrocytes and neurons

Funding Type: 
SEED Grant
Grant Number: 
RS1-00365
ICOC Funds Committed: 
$0
Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 
Suppression of rejection of embryonic stem cells and their derivatives. Human embryonic stem cells (hESC) hold great promise in the treatment of human disease since they can give rise to cells that are lost during disease. In particular, we have the capability to induce the differentiation of hESC into oligodendrocytes and neurons, which may be useful in treatment of a variety of neurological diseases. A significant problem may arise in the long-term survival of hESC-derived oligodendrocytes or neurons, however, due to rejection mediated by cytotoxic T cells (CTL) of the host immune system. Medicinal suppression of the immune system is useful, but has attendant adverse side-effects. In contrast, viruses escape CTL mediated immunity by down-regulating the expression of HLA-A and B cell surface molecules on infected cells. We will mimic this strategy using siRNA, a strategy for which the 2006 Nobel prize in Physiology or Medicine was awarded. HLA-A and B negative and control cells will be introduced into rats subjected to thoracic spinal cord contusion injury, a model that has been used extensively by our collaborator. Survival of experimental and control oligodendrocytes and neurons will be assayed by immunohistology of tissue derived from the site of injury and human cell engraftment. Our approach may be useful in prolonging the survival of hESC-derived cells of all lineages and for all uses, since nearly all cells express MHC-I glycoproteins. Our work is particularly relevant to treatment of spinal cord injury, multiple sclerosis and Parkinson’s disease as well as other diseases where loss of neurons or oligodendrocytes causes adverse effects.
Statement of Benefit to California: 
Our work will directly benefit the citizens of California since all clinical uses of of human embryonic stem cells (hESC) will benefit from increased survival of hESC and their derivatives. In particular we will modify hESC-derived brain cells (oligodendrocytes and neurons) to survive longer in patients. These cells will be useful in treating spinal cord injury, multiple sclerosis and Parkinson's disease, which together affect 125,000 to 250,000 people in the state of California.
Progress Report: 
  • Human embryonic stem cells (hESCs) can be changed into virtually any cell type in the adult body. Because of this unique capability, these cells have the potential to cure many human diseases. Several hurdles exist and need to be overcome before results from the exciting field of stem cell research can be used in the clinic. One of these hurdles is that the change of stem cells into differentiated cells often produces a complicated mixture, consisting of cells from several different tissue types. A current challenge at the forefront of hESC research is to obtain pure differentiated cells that can be used for medical applications. For example, nerve cells may be required for repairing spinal cord damage. Our research focuses on finding ways to identify neuronal cells and their precursors from amongst the cacophony of stem cell differentiation products. In the past year, we have discovered several markers of neuronal differentiation. These markers may be important for understanding basic biological functions of stem cells.
  • Human embryonic stem cells (hESCs) can be changed into virtually any cell type in the adult body. Because of this unique capability, these cells have the potential to cure many human diseases. Several hurdles exist and need to be overcome before results from the exciting field of stem cell research can be used in the clinic. One of these hurdles is that the change of stem cells into differentiated cells often produces a complicated mixture, consisting of cells from several different tissue types. A current challenge at the forefront of hESC research is to obtain pure differentiated cells that can be used for medical applications. For example, nerve cells may be required for repairing spinal cord damage. Our research focuses on finding ways to identify neuronal cells and their precursors from amongst the cacophony of stem cell differentiation products. In the past year, we have discovered several markers of neuronal differentiation. These markers may be important for understanding basic biological functions of stem cells.

© 2013 California Institute for Regenerative Medicine