Mouse MFGE8^high Skeletal Stem Cells Drive Osteogenesis via Matrix Mechanics

Area of Science:

• Biomedical Engineering
• Stem Cell Biology
• Oral and Maxillofacial Surgery

Background:

• Jawbone defect regeneration is hindered by poorly understood regional differences in mandibular osteogenesis.
• Skeletal stem cells (SSCs) play a critical role in bone formation, but their regional specialization is unclear.

Purpose of the Study:

• To investigate the intrinsic programs of mouse mandibular skeletal stem cells (SSCs) that explain regional differences in osteogenesis.
• To identify molecular mechanisms driving enhanced osteogenic capacity in specific mandibular regions.

Main Methods:

• Single-cell RNA sequencing of mouse mandibular cells to analyze cell composition and gene expression.
• In vitro and in vivo assays to compare the osteogenic capacity of SSCs from different mandibular regions.
• Molecular analyses including MFGE8 knockdown/recombinant protein application, integrin and FAK signaling pathway inhibition.

Main Results:

• A ramus-enriched SSC population with high MFGE8 expression was identified, exhibiting superior osteogenic capacity.
• MFGE8 positively regulates osteogenic differentiation of SSCs by modulating extracellular matrix (ECM) properties and integrin-dependent signaling.
• MFGE8 interacts with integrin β3, promoting FAK phosphorylation and enhancing ECM viscoelasticity, crucial for osteogenesis.

Conclusions:

• MFGE8 is a key regulator of osteogenic capacity in ramus-derived SSCs, influencing ECM biomechanics.
• MFGE8-mediated integrin-FAK signaling is essential for coupling matrix remodeling to enhanced jawbone regeneration.
• Targeting MFGE8 and associated signaling pathways holds promise for improving jawbone defect repair.