Remyelination of chronic demyelinated lesions with directly induced neural stem cells
Luca Peruzzotti‐Jametti, Nunzio Vicario, Giulio Volpe, Sandra Rizzi, Cheek Kwok, Ivan Lombardi, Mads S. Bergholt, Lucas Barea‐Moya, Andrea D’Angelo, Alexandra M. Nicaise, Giuseppe D’Amico, Grzegorz Krzak, Cory M. Willis, Sara Gil‐Perotín, Olena Hruba, Alice Braga, Molly M Stevens, José Manuel García‐Verdugo, Kourosh Saeb‐Parsy, Chao Zhao, Robin J.M. Franklin, Frank Edenhofer, Stefano Pluchino
Abstract
The limited ability of CNS progenitor cells to differentiate into oligodendrocytes limits the repair of demyelinating lesions and contributes to the disability of people with progressive multiple sclerosis (PMS). Neural stem cell (NSC) transplantation has emerged as a safe therapeutic approach in people with PMS, where it holds the promise of healing the injured CNS. However, the mechanisms by which NSC grafts could promote CNS remyelination need to be carefully assessed before their widespread clinical adoption. In this study, we used directly induced NSCs (iNSCs) as a novel transplantation source to boost remyelination in the CNS. Using a mouse model of focal lysophosphatidylcholine (LPC)-induced demyelination, we found that mouse iNSCs promote remyelination by enhancing endogenous oligodendrocyte progenitor cells differentiation and by directly differentiating into mature oligodendrocytes. Transplantation of mouse iNSCs in LPC-lesioned Olig1-/- mice, which exhibits impaired remyelination, confirmed the direct remyelinating ability of grafts and the formation of new exogenous myelin sheaths. We also demonstrated that the xenotransplantation of human iNSCs (hiNSCs) is safe in mice, with hiNSCs persisting long-term in demyelinating lesions where they can produce graft-derived human myelin. Our findings support the use of NSC therapies to enhance remyelination in chronic demyelinating disorders, such as PMS.