Single cell RNA-seq analysis associates Osm signaling in macrophages with osteogenic differentiation during heterotopic ossification.

Abstract

Heterotopic ossification (HO) is an abnormal tissue repair program that occurs after musculoskeletal injury and involves the formation of ectopic bone within soft tissues, and the cellular and molecular mechanisms underlying its development are currently unclear. We investigated the relationship between local inflammatory microenvironment and osteogenic differentiation of mesenchymal progenitor cells (MPC) in trauma-induced HO mice by single-cell transcriptomics. We revealed diverse phenotypes of MPCs and macrophages in HO, and showed that macrophage-derived Osm was associated with aberrant chondrogenic progenitor cell differentiation. Furthermore, Spi1, as a novel regulator of early macrophage activation and regulation of Osm expression in HO, which activates M1 macrophages after initial injury thereby contributing to HO formation. Our findings provide novel insights into understanding the functional impact of macrophages on MPC fate, and we also believe that this may offer new therapeutic opportunities to reduce HO risk by targeting macrophage-driven aberrant progenitor cell differentiation.