N2-Polarized Neutrophils Guide Bone Mesenchymal Stem Cell Recruitment and Initiate Bone Regeneration: A Missing Piece of the Bone Regeneration Puzzle

The role of neutrophils in bone regeneration remains elusive. In this study, it is shown that intramuscular implantation of interleukin-8 (IL-8) (commonly recognized as a chemotactic cytokine for neutrophils) at different levels lead to outcomes resembling those of fracture hematoma at various stages. Ectopic endochondral ossification is induced by certain levels of IL-8, during which neutrophils are recruited to the implanted site and are N2-polarized, which then secrete stromal cell-derived factor-1 alpha (SDF-1 alpha) for bone mesenchymal stem cell (BMSC) chemotaxis via the SDF-1/CXCR4 (C-X-C motif chemokine receptor 4) axis and its downstream phosphatidylinositol 3'-kinase (PI3K)/Akt pathway and beta-catenin-mediated migration. Neutrophils are pivotal for recruiting and orchestrating innate and adaptive immunocytes, as well as BMSCs at the initial stage of bone healing and regeneration. The results in this study delineate the mechanism of neutrophil-initiated bone regeneration and interaction between neutrophils and BMSCs, and innate and adaptive immunities. This work lays the foundation for research in the fields of bone regenerative therapy and biomaterial development, and might inspire further research into novel therapeutic options.

Automated summary

This study reveals the critical role of neutrophils in bone regeneration, where levels of IL-8 implanted intramuscularly lead to outcomes resembling fracture hematoma, and certain levels induce ectopic endochondral ossification. Neutrophils are pivotal in recruiting and orchestrating immune cells and BMSCs at the initial stage of bone healing.