ABSTRACT
Despite extensive progress in immunotherapies that reduce inflammation and relapse rate in patients with multiple sclerosis (MS), preventing disability progression associated with cumulative neuronal/axonal loss remains an unmet therapeutic need. Complementary approaches have established that remyelination prevents degeneration of demyelinated axons. While several pro-remyelinating molecules are undergoing preclinical/early clinical testing, targeting these to disseminated MS plaques is a challenge. In this context, we hypothesized that monocyte (blood) -derived macrophages may be used to efficiently deliver repair-promoting molecules to demyelinating lesions. Here, we used transplantation of genetically-modified hematopoietic stem cells (HSCs) to obtain circulating monocytes that overexpress Semaphorin 3F, a pro-remyelinating molecule. We show that Semaphorin 3F-expressing macrophages quickly infiltrate demyelinating spinal cord lesions, which increases oligodendrocyte progenitor cell recruitment and accelerates myelin repair. Our results provide a proof-of-concept that monocyte-derived macrophages could be used to deliver pro-remyelinating agents “at the right time and place”, suggesting novel means for remyelinating therapies in patients with MS.
Competing Interest Statement
VT, GDC, MSA, BGL, ST, LI-nothing to disclose. NC- Scientific advisor for Asklepios Biopharmaceutics. Collaboration with Bluebird Bio; CL- participation to advisory boards for Roche, Biogen, Merck-Serono, Genzyme, Vertex, Rewind; scientific collaboration with Vertex and Merck Serono.
Footnotes
1 ONE SENTENCE SUMMARY: Targeted delivery of Semaphorin 3F by genetically-modified macrophages accelerates OPC recruitment and improves myelin regeneration
↵† senior co-authors