Oligodendrocytes wrap nerve fibers in the central nervous system with layers of specialized cell membrane to form myelin sheaths1. Myelin is destroyed by the immune system in multiple sclerosis, but myelin is thought to regenerate and neurological function can be recovered. In animal models of demyelinating disease, myelin is regenerated by newly generated oligodendrocytes, and remaining mature oligodendrocytes do not appear to contribute to this process2–4. Considering the major differences in oligodendrocyte generation dynamics and adaptive myelination between rodents and humans5–9, it is uncertain how well experimental animals reflect the situation in multiple sclerosis. We have assessed the generation dynamics of oligodendrocytes in multiple sclerosis patients by measuring the integration of nuclear bomb test derived 14C in genomic DNA10. The generation of new oligodendrocytes was increased several-fold in normal appearing white matter in a subset of individuals with very aggressive disease, but not in the majority of subjects with multiple sclerosis, demonstrating an inherent potential to substantially increase oligodendrocyte generation but that this fails in most patients. Oligodendrocytes in shadow plaques, thinly myelinated lesion that are thought to represent remyelinated areas, were old in multiple sclerosis patients. The absence of new oligodendrocytes in shadow plaques suggests that remyelination of lesions occur transiently or not at all, or that myelin is regenerated by preexisting, and not new, oligodendrocytes in multiple sclerosis. We report unexpected oligodendrocyte generation dynamics in multiple sclerosis, which should guide the use of current, and the development of new, therapies.

The spatial distribution of lymphocyte clones within tissues is critical to their development, selection, and expansion. We have developed Spatial Transcriptomics of VDJ sequences (Spatial VDJ), which maps immunoglobulin and TR antigen receptors in human tissue sections. Spatial VDJ captures lymphocyte clones matching canonical T, B, and plasma cell distributions in tissues and amplifies clonal sequences confirmed by orthogonal methods. We confirm spatial congruency between paired receptor chains, develop a computational framework to predict receptor pairs, and link the expansion of distinct B cell clones to different tumor-associated gene expression programs. Spatial VDJ delineates B cell clonal diversity, class switch recombination, and lineage trajectories within their spatial context. Taken together, Spatial VDJ captures lymphocyte spatial clonal architecture across tissues, which could have important therapeutic implications.One-Sentence SummarySpatial transcriptomics-based technology co-captures T and B cell receptors within their anatomical niche in human tissue.

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