Aldh1L1 Lineage Cells Contribute to the Functional Heterogeneity Within the Cells in Glial Scars After Spinal Cord Injury Through YAP Signaling

ABSTRACT Injury to the central nervous system (CNS) such as spinal cord results in multifaceted cellular responses, including the glial scars, a structural formation of reactive glia around an area of severe tissue damage. However, the functional heterogeneity within the cells in glial scars remains unclear. In this study, we found Aldh1L1 lineage cells exhibited reactive astrocyte distribution, culminating in glial scar formation via proliferation and differentiation after SCI. Interestingly, the Aldh1L1 + glial scars were distinct from the GFAP + glial scars, encircled an area closer to the injury center and harbored scattered Aldh1L1 lineage cells within the central zone. At day 7 after SCI, Aldh1L1 lineage cells reached peak activation; some of them exhibited an injury responsive intermediate state with neural stem cell‐like properties, and a significant portion of the Aldh1L1 + glial scar arose from the differentiation and migration of central canal ependymal cells, not derived from invading meningeal cell lineages or pial astroglia. Some of the Aldh1L1 + cells in glial scar exhibited expression of oligodendrocyte progenitor cell markers. Mechanistically, YAP was highly expressed and activated in Aldh1L1 + cells after SCI, and YAP deletion in Aldh1L1 + cells inhibited glial scar formation and differentiation into astrocytes from Aldh1L1 + ependymal cells, exacerbated neuronal loss, and inhibited the functional recovery of mice after SCI. These results suggest that Aldh1L1 lineage cells contribute to the functional heterogeneity within the cells in glial scars after SCI and uncover the pivotal role of YAP signaling in the formation of glial scars derived from Aldh1L1 lineage cells.