2. Academic Validation
  3. Adipose-derived stem cells attenuate rheumatoid arthritis by restoring CX3CR1+ synovial lining macrophage barrier

Adipose-derived stem cells attenuate rheumatoid arthritis by restoring CX3CR1+ synovial lining macrophage barrier

  • Stem Cell Res Ther. 2025 Mar 5;16(1):111. doi: 10.1186/s13287-025-04144-5.
Lei Wang 1 2,  Ming Hao 2,  Yongyue Xu 1 2,  Zhaoyan Wang 1 2,  Hanqi Xie 1 2,  Bo Zhang 1 2,  Xue Zhang 1 2,  Jun Lin 3,  Xiaodan Sun 4 5 6,  Jianbin Wang 2,  Qiong Wu 7 8
Affiliations

Affiliations

  • 1 MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, Tsinghua University, Beijing, 100084, China.
  • 2 School of Life Sciences, Tsinghua University, Beijing, 100084, China.
  • 3 Department of Orthopaedics, Suzhou Dushu Lake Hospital, The Fourth Affiliated of Soochow University, Medical Center of Soochow University, Suzhou, 215001, Jiangsu, China.
  • 4 School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, China.
  • 5 Key Laboratory of New Ceramics and Fine Processing, Tsinghua University, Beijing, 100084, China.
  • 6 Key Laboratory of Advanced Materials of Ministry of Education of China, Tsinghua University, Beijing, 100084, China.
  • 7 MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, Tsinghua University, Beijing, 100084, China. wuqiong@tsinghua.edu.cn.
  • 8 School of Life Sciences, Tsinghua University, Beijing, 100084, China. wuqiong@tsinghua.edu.cn.
PMID: 40038808 DOI: 10.1186/s13287-025-04144-5
Abstract

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease and the integrity of CX3CR1+ synovial macrophage barrier significantly impacts its progression. However, the mechanisms driving the dynamic changes of this macrophage barrier remain unclear. Traditional drug therapies for RA have substantial limitations. Mesenchymal stem cells (MSCs)-based cell therapy, especially adipose-derived stem cells (ADSCs), hold therapeutic promise. Nevertheless, the underlying therapeutic mechanism of ADSCs, especially their interactions with CX3CR1+ macrophages, require further investigation.

Methods: To explore the interaction between ADSCs and CX3CR1+ synovial macrophages during barrier reconstruction, underlying the therapeutic mechanism of ADSCs and the mechanisms on the dynamic changes of the macrophage barrier, scRNA-seq analysis was conducted 4 days after ADSCs injection in serum transfer-induced arthritis model mice. The roles of mitochondria transfer and ADSCs transplantation were also explored. Bulk RNA-seq analysis was performed after the co-culture of ADSCs and CX3CR1+ synovial macrophages. To study the in vivo fate of ADSCs, bulk RNA-seq was performed on ADSCs retrieved at 0, 2, 4, and 7 days post-injection.

Results: Intra-articular injection of ADSCs effectively attenuated the pathological progression of mice with serum transfer-induced arthritis. ADSCs gradually adhered to CX3CR1+ macrophages, facilitating the restore of the macrophage barrier, while the absence of this barrier greatly weakened the therapeutic effect of ADSCs. scRNA-seq analysis revealed an Atf3high Ccl3high subset of CX3CR1+ macrophages with impaired Oxidative Phosphorylation that increased during RA progression. ADSCs-mediated reduction of this subset appeared to be linked to mitochondrial transfer, and transplantation of isolated ADSCs-derived mitochondria also proved effective in treating RA. Both bulk RNA-seq and scRNA-seq analyses revealed multiple interaction mechanisms between ADSCs and CX3CR1+ macrophages, including CD74/Mif axis and GAS6/MERTK axis, which contribute to barrier restoration and therapeutic effects. Furthermore, bulk RNA-seq analysis showed that ADSCs primarily contribute to tissue repair and immune regulation subsequently.

Conclusions: Our results suggest that ADSCs ameliorated the energy metabolism signature of CX3CR1+ lining macrophages and may promote barrier restoration through mitochondria transfer. In addition, we elucidated the fate of ADSCs and the therapeutic potential of mitochondria in RA treatment.

Keywords

Macrophage; Mesenchymal stem cells; Mitochondria; Rheumatoid arthritis.

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