Rheumatoid arthritis (RA) is characterized by chronic inflammation and joint degradation. The integrity of the CX3CR1+ synovial macrophage barrier has been identified as a critical factor in RA progression. However, the underlying mechanisms driving changes in this barrier remain insufficiently understood.
A study explored the potential of adipose-derived stem cells (ADSCs) in modulating synovial macrophage function and mitigating RA. Researchers utilized a serum transfer-induced arthritis mouse model to assess the effects of ADSC therapy. Following intra-articular injection, ADSCs adhered to CX3CR1+ macrophages, promoting the reconstruction of the macrophage barrier. The absence of this barrier significantly weakened the therapeutic impact of ADSCs, suggesting that their efficacy is closely tied to macrophage integrity.
Single-cell RNA sequencing (scRNA-seq) analysis identified a subset of CX3CR1+ macrophages (Atf3^high Ccl3^high) with impaired oxidative phosphorylation that increased in response to RA progression. ADSC therapy appeared to reduce this subset, a process linked to mitochondrial transfer. Notably, transplantation of isolated ADSC-derived mitochondria alone also showed therapeutic potential, highlighting a possible mechanism by which ADSCs contribute to tissue repair.
Further RNA sequencing analysis revealed multiple interaction pathways between ADSCs and CX3CR1+ macrophages, particularly the Cd74/Mif and GAS6/MERTK signaling axes. These interactions suggest that ADSCs not only restore the macrophage barrier but also contribute to broader immune modulation and tissue repair processes in RA.
The study also investigated the in vivo fate of ADSCs, finding that they primarily support tissue repair and immune regulation over time. These findings add to the growing body of research on MSC-based therapies and suggest that ADSCs may serve as a valuable tool in modulating immune responses in RA.
