Injury to the CNS leads to formation of scar tissue, which is important in sealing the lesion and inhibiting axon regeneration. The fibrotic scar that comprises a dense extracellular matrix is thought to originate from meningeal cells surrounding the CNS. However, using transgenic mice, we demonstrate that perivascular collagen1α1 cells are the main source of the cellular composition of the fibrotic scar after contusive spinal cord injury in which the dura remains intact. Using genetic lineage tracing, light sheet fluorescent microscopy, and antigenic profiling, we identify collagen1α1 cells as perivascular fibroblasts that are distinct from pericytes. Our results identify collagen1α1 cells as a novel source of the fibrotic scar after spinal cord injury and shift the focus from the meninges to the vasculature during scar formation.

The wound healing process that occurs after spinal cord injury is critical for maintaining tissue homeostasis and limiting tissue damage, but eventually results in a scar-like environment that is not conducive to regeneration and repair. A better understanding of this dichotomy is critical to developing effective therapeutics that target the appropriate pathobiology, but a major challenge has been the large cellular heterogeneity that results in immensely complex cellular interactions. In this study, we used single-cell RNA sequencing to assess virtually all cell types that comprise the mouse spinal cord injury site. In addition to discovering novel subpopulations, we used expression values of receptor–ligand pairs to identify signaling pathways that are predicted to regulate specific cellular interactions during angiogenesis, gliosis, and fibrosis. Our dataset is a valuable resource that provides novel mechanistic insight into the pathobiology of not only spinal cord injury but also other traumatic disorders of the CNS.

Although infiltrating macrophages influence many pathological processes after spinal cord injury (SCI), the intrinsic molecular mechanisms that regulate their function are poorly understood. A major hurdle has been dissecting macrophage-specific functions from those in other cell types as well as understanding how their functions change over time. Therefore, we used the RiboTag method to obtain macrophage-specific mRNA directly from the injured spinal cord in mice and performed RNA sequencing to investigate their transcriptional profile. Our data show that at 7 d after SCI, macrophages are best described as foam cells, with lipid catabolism representing the main biological process, and canonical nuclear receptor pathways as their potential mediators. Genetic deletion of a lipoprotein receptor, CD36, reduces macrophage lipid content and improves lesion size and locomotor recovery. Therefore, we report the first macrophage-specific transcriptional profile after SCI and highlight the lipid catabolic pathway as an important macrophage function that can be therapeutically targeted after SCI.SIGNIFICANCE STATEMENTThe intrinsic molecular mechanisms that regulate macrophage function after spinal cord injury (SCI) are poorly understood. We obtained macrophage-specific mRNA directly from the injured spinal cord and performed RNA sequencing to investigate their transcriptional profile. Our data show that at 7 d after SCI, macrophages are best described as foam cells, with lipid catabolism representing the main biological process and canonical nuclear receptor pathways as their potential mediators. Genetic deletion of a lipoprotein receptor, CD36, reduces macrophage lipid content and improves lesion size and locomotor recovery. Therefore, we report the first macrophage-specific transcriptional profile after SCI and highlight the lipid catabolic pathway as an important macrophage function that can be therapeutically targeted after SCI.

NG2 cells, also known as oligodendrocyte progenitor cells, are located throughout the central nervous system and serve as a pool of progenitors to differentiate into oligodendrocytes. In response to spinal cord injury, NG2 cells increase their proliferation and differentiation into remyelinating oligodendrocytes. While astrocytes are typically associated with being the major cell type in the glial scar, many NG2 cells also accumulate within the glial scar but their function remains poorly understood. Similar to astrocytes, these cells hypertrophy, upregulate expression of chondroitin sulfate proteoglycans, inhibit axon regeneration, contribute to the glial-fibrotic scar border, and some even differentiate into astrocytes. Whether NG2 cells also have a role in other astrocyte functions, such as preventing the spread of infiltrating leukocytes and expression of inflammatory cytokines, is not yet known. Thus, NG2 cells are not only important for remyelination after spinal cord injury, but are also a major component of the glial scar with functions that overlap with astrocytes in this region. In this review, we describe the signaling pathways important for the proliferation and differentiation of NG2 cells, as well as the role of NG2 cells in scar formation and tissue repair.