Progressive forms of multiple sclerosis (MS) are associated with chronic demyelination in the central nervous system (CNS). Unlike patients with relapsing-remitting forms of this disease (RRMS) in which remyelination can be identified, progressive forms of MS generally do not exhibit brain repair. Further, when RRMS patients transition from relapsing disease to secondary progressive disease (SPMS), and also those patients with primary progressive disease (PPMS) typically do not benefit from current immunomodulatory therapies which can effectively alleviate symptoms in RRMS patients. Promoting endogenous brain repair is viewed as a potential strategy to foster myelination and restore neurologic function in MS patients with progressive forms of this disease. 

To better understand the basis of myelin pathology in MS, we recently reported the development and characterization of novel iPS cell lines from PPMS patients’ blood samples and studied the cellular impact of disease compared with age-matched, non-diseased blood relative or spousal blood iPS cell lines. Based on our previous studies, we differentiated iPS cells into neural progenitor cells (NPCs) since NPCs are found in demyelinated lesions in MS, NPCs are known to secrete factors that promote myelination, and NPCs are known to provide neuroprotection and foster myelin repair in animal models of demyelination. We reported that iPS-derived NPCs from PPMS patients did not promote oligodendrocyte progenitor cell (OPC) maturation in vitro nor did PPMS NPCs provide neuroprotection against demyelination in a cuprizone-mouse model of CNS demyelination. To better understand why PPMS NPCs differed from age-matched control NPCs, we examined the NPC secretome and determined that PPMS NPCs exhibited increased production of specific factors linked to cellular aging.

Our  data suggest cellular senescence is a disease-associated phenotype in MS. Our soon to be published data also demonstrate that cellular senescence in the PPMS NPCs is reversible. Comparative proteomic analyses of the conditioned media from control and PPMS NPCs has also identified a candidate factor we find to be responsible for impairing oligodendrocyte differentiation. Based on these new data, we hypothesize that impaired CNS remyelination in MS is a consequence of disease-acquired cellular senescence in NPCs that, through production of secreted factors, limits the endogenous regenerative potential of OPCs. This project will investigate whether all forms of MS NPCs fail to provide neuroprotection, but also whether MS NPCs block endogenous CNS remyelination from occurring; determine whether reversal of cellular senescence in MS NPCs can restore function to enhance OPC maturation and CNS myelination both in vitro and in vivo; and, interrogate the secretome NPCs to identify putative  OPC maturation regulatory factors using both in vitro and in vivo model systems. Results from this study are expected to determine whether targeting cellular senescence may be a therapeutic strategy to promote remyelination in MS patients which may have implications for understanding why remyelination failure diminished with age and in this disease.