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