Directed Stem Cell Recruitment into the CNS in Response to Coxsackievirus Infection
Improved and more effective treatment strategies to alleviate the clinical symptoms associated with multiple sclerosis (MS) remain problematic. A better understanding of stem cell migration across the blood-cerebral spinal fluid (CSF)-barrier and targeted differentiation may assist clinicians and researchers in maximizing the efficacy of stem cell based therapies. Many previous studies utilizing stem cell therapy for tissue regeneration have relied on the seemingly inherent ability of stem cells to migrate and differentiate somewhat haphazardly into predetermined areas in damaged tissues. However, the random inoculation and migration of stem cells, regardless of regenerative potential, is unlikely to lead to the most efficient recruitment of stem cells and subsequent repair of critically damaged regions . Utilizing our neurotropic viral infection model which appears to induce the recruitment of peripheral stem cells, we will attempt to characterize stem cell migration across the blood-CSF-barrier and determine necessary recruitment factors upregulated during infection. Additionally, we will test the ability and advantages of utilizing an attenuated recombinant coxsackievirus as a novel viral vector for gene transfer into stem cells. The ability to insert foreign genes into stem cells may assist in proper stem cell differentiation and protection from the host immune response. Finally, we will evaluate the therapeutic use of stem cells transduced with an attenuated recombinant coxsackievirus utilizing a relapsing-remitting mouse model of MS. MS is thought to be an autoimmune disease in which the loss of myelin contributes to central nervous system (CNS) damage and clinical disease. Stem cell transplantation may be a therapeutic approach for the re-establishment of myelinated axonal fibers and proper neuronal function. The addition of foreign genes into stem cells may help protect the newly differentiated cells from suffering from the same fate as their non-functioning neighbor cells. We hope that the proposed research will assist in the development of novel reagents for optimized stem cell therapy in patients suffering from neurological diseases.
Approximately 400,000 Americans suffer from the neurological symptoms associated with multiple sclerosis (MS). The therapeutic use of stem cells may provide the basis for improving the lives of patients suffering from MS, and a variety of other neurological diseases. However, much remains to be understood regarding productive stem cell migration and proper differentiation of oligodendrocytes in the host. Oligodendrocytes are essential cells in the central nervous system (CNS) that help to protect the axons of nerve fibers by producing a fatty tissue called myelin. In MS, myelin is lost in many region of the CNS thereby producing sclerotic lesions. Hence, the ability to promote new myelin formation in damage regions by the addition of new oligodendrocytes may be a potential therapy for the alleviated the effects of clinical disease. The project will provide new insights on how stem cells may traverse through the blood-brain-barrier and differentiate into the various cell types found within the CNS. Furthermore, we will test the ability of using a well characterized coxsackievirus that efficiently infects stem cells as a viral gene delivery system. Our hope is that the information gained from our efforts will point to new directions, whereby optimized stem cell therapy may be of great benefit to those suffering from MS, and other neurological disabilities.