Human embryonic stem cells (hESC) provide a promising future therapeutic approach for replacement of diseased or damaged tissue. This proposal addresses the development of therapeutic strategies that can specifically aid two different neurological disorders. Multiple sclerosis (MS) is a chronic condition which affects the brain and spinal cord. In patients with this condition, the myelin sheaths that cover nerve fibers are erroneously destroyed by the body’s own immune system. In spinal cord injuries, the resulting inflammation causes severe damage to myelin-producing cells. The goal of this proposal is to determine if stem cells, at various phases of differentiation to myelin-producing cells, have characteristics which could not only replenish the lost myelin, but also confer a healing microenvironment. The focus will be on two beneficial immune-based processes. First specific aim will determine molecular signaling pathways involved in innate immune responses in hESC and establish if these processes provide a microenvironment conducive to tissue regeneration. Innate-immune responses have been shown to underlie tissue repair gene expression by dying cells. Our preliminary experiments have identified that components of this pathway are present in human embryonic stem cells (hESC), particularly at the later phases of differentiation to mature myelin-producing cells. Levels of factors involved in this process will be evaluated in hESC. To further establish the potential of the hESC to create a regenerative microenvironment for damaged cells, inserts of stressed and dying cells will be co-cultured with hESC. Cell viability, with or without co-exposure to hESC, will be determined using a commercially available cell cytotoxicity assay. The hypothesis to be tested is that hESC can provide a restorative microenvironment for stressed or dying cells and this involves up-regulation of innate immune responses. In the second specific aim, we will evaluate whether hESC can down regulate harmful inflammatory immune responses by a process used by fetal cells to escape the maternal immune response. This process is called ‘immune tolerance. To determine if hESC have the ability to provide an immune privileged microenvironment (similar to the fetus) components of this response will be determined in hESC. The hypothesis to be tested is that hESC can subvert destructive immune responses by processes similar to those that underlie immune tolerance. The long term objective of these studies is to design oligodendrocyte populations derived from hESC that provide an ideal microenvironment for promotion of cell survival, regeneration, and immune tolerance. These can eventually be used therapeutically in chronic demyelinating diseases such as MS or acute traumatic spinal cord injuries with minimal chances of host rejection.
Statement of Benefit to California:
The proposed research will benefit California and its citizens in several ways. First, the results may aid in the design of effective therapies based on hESC that can benefit patients with multiple sclerosis or spinal cord injury. For the citizens of California who are suffering from these disorders, the development of these stem cell-based therapies will alleviate some of the pain and hardships associated with their condition. Second, successful development of stem-cell based therapies will lighten the economic burden for the state of California, which provides health care services to its citizens. Third, the results gained from the studies proposed may lead to intellectual property rights which can be used as a foundation for creating new biotechnology companies. This will not only create jobs but will also contribute to the economic growth of the state of California.