Abstract
Spinal cord injury (SCI) triggers a highly heterogeneous and spatially dynamic wound response involving diverse myeloid and fibroblast populations. Here, we integrate high-resolution single-cell and spatial transcriptomics with novel genetic lineage tracing models to define the cellular composition of the spinal cord after injury, its temporal dynamics, and age-dependent molecular pathology of the SCI microenvironment.
We identify previously unrecognized complexity within the myeloid cell subtypes, expanding on our initial analyses. Spatial mapping reveals that BAMs infiltrate the lesion epicenter and are positioned, even prior to injury, to act as early fibroblast activators—a role supported by colocalization analyses. Mature inflammatory macrophages dominate fibroblast interactions by 7 days post-injury (dpi), though immature monocytes do persist in the epicenter of the fibrotic scar, while microglia segregate into distinct proliferative and interferon-responsive populations which corral the fibroblasts. Notably, discrete “interferon islands” emerge throughout tissue distal to the lesion, indicating long-range perturbations in otherwise spared regions.
The fibrotic scar was originally thought to be the result of the meninges being physically displaced into the parenchyma, though analyses by our lab demonstrated that the fibrotic scar develops even in the non-penetrating contusive injury, where perivascular fibroblasts are visualized delaminating from local vessels. Now, with the application of a larger scale single cell dataset and new genetic lineage tracing tools, we find that a combination of unique fibroblast niches contribute to the development and persistence of the scar...