Augmentation of a neuroprotective myeloid state by hematopoietic cell transplantation

Multiple sclerosis (MS) is an autoimmune disease associated with inflammatory demyelination in the central nervous system (CNS). Autologous hematopoietic cell transplantation (HCT) is under investigation as a promising therapy for treatment-refractory MS. Here we show that the enhancement of a reactive myeloid response following HCT is neuroprotective in chronic experimental autoimmune encephalitis (EAE). Myeloid cells are the CNS population with the strongest transcriptional changes in chronic EAE, which are further promoted by HCT. HCT leads to clinical improvement, reduction in demyelinated lesions, and amelioration of reactive astrogliosis reflected in reduced expression of EAE-associated gene signatures in oligodendrocytes and astrocytes. Enhanced incorporation of circulation-derived myeloid cells into the CNS results in a more consistent therapeutic effect corroborated by additional amplification of HCT-induced transcriptional changes, underlining myeloid-derived beneficial effects in the chronic phase of EAE. Replacement or manipulation of CNS myeloid cells thus represents an intriguing therapeutic direction for inflammatory demyelinating disease. Single-nuclei RNA transcriptomes of spinal cords obtained from healthy control (control) or mice with experimental autoimmune encephalomyelitis (EAE) using 10x Genomics Drop-seq (v3.1). EAE mice were further divided in experimental groups with either no treatment, bone marrow transplantation, or bone marrow transplantation in combination with CSF1R inhibitor (PLX)