Csf1r⁻ macrophages govern the second wave of neutrophils for bone repair

TL;DR

A specific type of macrophage helps repair bone by recruiting neutrophils and promoting cell growth through Wnt and activin signaling.

Contribution

Discovery of osteodirective macrophages (OdMacs) and their role in recruiting preneutrophils to enhance bone regeneration.

Findings

OdMacs recruit activin A-expressing preneutrophils to bone injury sites.

Wnt signaling in bone marrow stromal cells and activin A from preneutrophils are critical for bone regeneration.

OdMacs form regenerative niches that could be targeted for regenerative therapies.

Abstract

Macrophages play a pivotal role in tissue regeneration, including bone healing; however, the mechanisms and cell types through which they establish regenerative niches are not yet fully understood. Here, we identified a distinct subset of osteodirective macrophages (OdMacs), characterized by the expression profile F4/80⁺ Csf1r⁻ Cx3cr1hi Ccr2hi, which contribute to the formation of bone regenerative niches following injury. Histological analysis and FACS analysis, combined with transcriptomic profiling (RNA-seq and scRNA-seq), revealed that OdMacs facilitate the recruitment of activin A-expressing preneutrophils (preNeu) to sites of bone injury. This recruitment enhances the proliferation and osteogenic differentiation of LepR⁺ bone marrow stromal cells (BMSCs), thereby promoting bone regeneration. Furthermore, genetic studies using Axin2-Cre; tdTomato, Inhba, and Wls conditional knockout mice underscored the essential roles of Wnt signaling in BMSCs and preNeu-derived activin A in orchestrating this regenerative process. The OdMac-regulated regenerative niche represents a promising therapeutic target for regenerative medicine.