Approximately 250,000 people in the United States are diagnosed with multiple sclerosis (MS). In patients with this condition, the white sheaths known as myelin that cover nerve fibers are erroneously destroyed by the body’s own autoreactive immune system. Patients diagnosed with MS fall into a spectrum ranging from benign, where individuals diagnosed may lead normal lives, to severe, where patients are progressively debilitated. The goal of this proposal is to determine if stem cells, at various phases of differentiation to myelin-producing oligodendrocytes, have characteristics which could not only replenish the lost myelin, but also confer a healing microenvironment for dying nerve cells. The focus will be on two beneficial immune-based processes. First specific aim will determine if innate immune responses, necessary for healing damaged tissue, are present in human embryonic stem cell (hESC)-derived oligodendrocytes and establish if these processes provide a microenvironment conducive to nerve cell survival. Innate-immune responses have been shown to underlie tissue repair of dying cells. Our preliminary experiments have identified that components of this pathway are present in hESC, particularly at the later phases of differentiation to mature oligodendrocytes. Levels of factors involved in this process will be evaluated. To further establish the potential of hESC to create a regenerative microenvironment for damaged cells, dying nerve cells will be grown with hESC-derived oligodendrocytes. Cell viability will be determined using a commercially available cell toxicity 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 prevent destruction by 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 hESC-derived oligodendrocyte cell populations 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 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 human embryonic stem cells 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.