Cell-replacement therapies to promote remyelination in JHMV-infected mice:
An important and clinically-relevant question related to demyelinating diseases is defining mechanisms that promote remyelination of demyelinated axons. We have previously shown that surgical engraftment of syngeneic neural progenitor cells (NPCs) into mice persistently infected with JHMV results in survival and migration of engrafted NPCs accompanied by extensive remyelination. We are the only group, to my knowledge, examining the therapeutic potential of cell replacement strategies using a viral model of demyelination. This is important in that the etiology of MS remains enigmatic and viruses have long been considered important as a potential triggering agent in inducing demyelinating diseases such as MS. Moreover, numerous viruses are capable of persisting within the CNS therefore understanding if NPCs are capable of promoting repair within this environment is critical. We have determined that transplanted cells migrate to areas of demyelination by responding to the specific chemokines expressed within areas of demyelination. We have employed 2-photon microscopy to visualize how engrafted NPCs physically engage demyelinated axons initiating differentiation into oligodendrocytes that results in remyelination. From these studies, we’ve also demonstrated that axonal damage precedes immune-mediated demyelination following viral infection of the CNS. These findings argue that demyelination is not a prerequisite for axonopathy. Ongoing studies within the laboratory will define mechanisms by which viral infection of the CNS initiates damage to axons. We are also investigating the therapeutic potential of human NPCs (hNPCs) in mediating functional recovery following transplantation into JHMV-infected mice. Our data indicates that hNPCs are immunosuppressive as evidenced by dramatic reduction in neuroinflammation accompanied by remyelination within the spinal cords of transplanted animals. These findings are provocative and indicate that hNPCs are therapeutic although rapidly rejected. This work is funded by NIH grants R01 NS099255, R01 NS092042 and and National MS Society Collaborative Center Grant CA-1607-25040.