CCL2/CCR2 Signalling in Mesenchymal Stem/Progenitor Cell Recruitment and Fracture Healing in Mice

Area of Science:

• Biomedical Engineering
• Immunology
• Regenerative Medicine

Background:

• Macrophage efferocytosis is vital for tissue repair and resolving inflammation.
• Efferocytosis by macrophages stimulates the secretion of specific signaling molecules.
• Understanding these secreted factors is key to improving regenerative therapies.

Purpose of the Study:

• To investigate the role of CCL2 secreted by efferocytic macrophages.
• To determine CCL2's effect on mesenchymal stem/progenitor cell (MSPC) migration.
• To analyze in vivo cell recruitment and bone healing in a CCL2 receptor-deficient model.

Main Methods:

• Utilized Ccr2-/- (KO) mice lacking CCL2 receptor signaling.
• Employed ossicle implants and ulnar stress fracture models for bone regeneration studies.
• Applied single-cell RNA sequencing, PCR, micro-CT, and immunohistochemistry for analysis.

Main Results:

• Efferocytosis upregulated CCL2 production by macrophages at bone injury sites.
• CCL2 gradients promoted MSPC migration through collagen matrices.
• KO mice showed reduced MSPC infiltration but increased macrophage infiltration in ossicle implants.
• CCR2 KO male mice exhibited enhanced bone formation in ulnar stress fractures.

Conclusions:

• CCL2 secretion by efferocytic macrophages influences stem cell recruitment.
• The impact of CCL2 on MSPC recruitment varies depending on the bone healing context.
• Targeting CCL2 signaling may offer differential therapeutic strategies for bone repair.