Macrophages support healing of ischemic injury by transdifferentiating towards mural cells and adopting functions important for vascular support

Abstract

Abstract Sterile inflammation following injury is important for tissue restoration. In injured human and mouse tissues, macrophages were recently found to accumulate perivascularly. This study investigates if macrophages adopt a mural cell identity important for restoration following ischemic injury. Single-cell RNA-sequencing of fate-mapped macrophages from ischemic mouse muscles demonstrates an identity switch of a subpopulation of macrophages with downregulated myeloid cell genes and upregulated mural cell genes. This macrophage-to-mural cell switch was further strengthened when including unspliced transcripts in the analysis. Induction of macrophage-specific PDGFRβ-deficiency prevented the perivascular macrophage phenotype, impaired vessel maturation and increased vessel leakiness, which ultimately reduced limb function. In conclusion, macrophages in adult ischemic tissue were demonstrated to undergo a transdifferentiation program to morphologically, transcriptomically and functionally resemble mural cells while losing their macrophage identity. The macrophage-to-mural cell switch is crucial for restored tissue function, and warrants exploration for future immunotherapies to enhance healing following injury.