Demyelination the loss of myelin that insulates and protects axons is a common pathological feature of many human neurodegenerative diseases including Multiple sclerosis (MS) and spinal cord injury. Chronic demyelination can ultimately lead to axonal loss, culminating in extensive disability through defects in neurologic function. The demyelination that defines many human neurodegenerative pathologies is progressive over time; however, studies indicate that myelin repair can occur during the course of some of diseases as well as animal models . 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, surgical transplantation of ES-derived human OPCs into sites of demyelination are directly capable of inducing remyelination of the damaged axons and/or modifying the local environment to stimulate and support remyelination by endogenous OPCs. Therefore, understanding the mechanisms by which engrafted huOPCs respond to the microenvironmental niche and survive is of critical importance to ensure the long-term survival and function of these cells for sustaining functional recovery. To this end, we have determined that the cytokine IFN-g promotes apoptosis (death) of human ES-derived OPCs and this is dependent, in part, through induction of the chemokine CXCL10. Importantly, we have insight into the molecular mechanisms by which IFN-g/CXCL10 mediates huOPC apoptosis. Moreover, we have made the novel observation that signaling through the chemokine receptor CXCR2 protects huOPCs from IFN-g/CXCL10-mediated death. Therefore, these findings highlight a previously unrecognized mechanism by which OPCs may protect themselves from death during chronic demyelinating diseases. The experiments outlined in this research proposal will further define the mechanisms associated with IFN-g/CXCL10 death as well as protection following CXCR2 signaling. The discoveries revealed from these experiments will potentially be clinically relevant as it may be possible to enhance survival of engrafted huOPCs as well as endogenous OPCs and thus increase the remyelination potential of these cells.
Statement of Benefit to California:
With over 37 million people, California is the most populated state in the US - and continues to grow. Combined with an increasing aged community, the medical demands placed on the health care workers will also continue to accelerate at a dramatic rate. As such, there will an increase in the number of neurologic diseases/injuries in which loss of myelin i.e. demyelination will be a common pathologic feature. Moreover, many of these demyelinating diseases will be chronic in which a patient may have symptoms associated with demyelination for a life-time. Therefore, interventional cell replacement therapies in which a remyelinating cell can be surgically engrafted into a human with a demyelinating disease represents a significant step forward for treatment of these devastating diseases. Indeed, the FDA has recently approved the use of oligodendrocyte progenitor cells (OPCs) derived from human embryonic stem (ES) cells for treatment of demyelination associated with spinal cord injury. A critical feature will be to understand how to sustain the long-term survival of the engrafted cells to insure functional recovery of the patient. This proposal will identify mechanisms associated with survival of OPCs derived from ES cells. Therefore, the long-term gain to California and its citizens that is derived from these experiments is i) the potential for increased health benefits derived from understanding how to sustain engrafted cell survival and improving the overall quality of life for these individuals; ii) increased productivity as a result of patients with demyelinating disease returning to work-force, iii)diminished economic burden on health care industry to care for patients with demyelinating diseases; and iv) employment for scientists/health care workers.