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

Kristel Parv, Carmen Herrera Hidalgo, Feifei Xu, Catarina Amoedo-Leite, Antoine Giraud, Daniel Holl, Cedric Seignez, Christian Goeritz, Gustaf Christoffersson, Mia Phillipson
2022 · doi:10.21203/rs.3.rs-2263892/v1
preprint OA: closed CC-BY-4.0
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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.

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License: CC-BY-4.0