Adipose-derived stem cells attenuate rheumatoid arthritis by restoring CX3CR1+ synovial lining macrophage barrier
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...
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BMC
2025-03-01
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| Series: | Stem Cell Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13287-025-04144-5 |
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| author | Lei Wang Ming Hao Yongyue Xu Zhaoyan Wang Hanqi Xie Bo Zhang Xue Zhang Jun Lin Xiaodan Sun Jianbin Wang Qiong Wu |
| author_facet | Lei Wang Ming Hao Yongyue Xu Zhaoyan Wang Hanqi Xie Bo Zhang Xue Zhang Jun Lin Xiaodan Sun Jianbin Wang Qiong Wu |
| author_sort | Lei Wang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-2ea2f314bf864d05bcbab419b9abeda6 |
| institution | DOAJ |
| issn | 1757-6512 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
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| series | Stem Cell Research & Therapy |
| spelling | doaj-art-2ea2f314bf864d05bcbab419b9abeda62025-08-20T03:05:52ZengBMCStem Cell Research & Therapy1757-65122025-03-0116111710.1186/s13287-025-04144-5Adipose-derived stem cells attenuate rheumatoid arthritis by restoring CX3CR1+ synovial lining macrophage barrierLei Wang0Ming Hao1Yongyue Xu2Zhaoyan Wang3Hanqi Xie4Bo Zhang5Xue Zhang6Jun Lin7Xiaodan Sun8Jianbin Wang9Qiong Wu10MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, Tsinghua UniversitySchool of Life Sciences, Tsinghua UniversityMOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, Tsinghua UniversityMOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, Tsinghua UniversityMOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, Tsinghua UniversityMOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, Tsinghua UniversityMOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, Tsinghua UniversityDepartment of Orthopaedics, Suzhou Dushu Lake Hospital, The Fourth Affiliated of Soochow University, Medical Center of Soochow UniversitySchool of Materials Science and Engineering, Tsinghua UniversitySchool of Life Sciences, Tsinghua UniversityMOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, Tsinghua UniversityAbstract 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.https://doi.org/10.1186/s13287-025-04144-5Mesenchymal stem cellsRheumatoid arthritisMacrophageMitochondria |
| spellingShingle | Lei Wang Ming Hao Yongyue Xu Zhaoyan Wang Hanqi Xie Bo Zhang Xue Zhang Jun Lin Xiaodan Sun Jianbin Wang Qiong Wu Adipose-derived stem cells attenuate rheumatoid arthritis by restoring CX3CR1+ synovial lining macrophage barrier Stem Cell Research & Therapy Mesenchymal stem cells Rheumatoid arthritis Macrophage Mitochondria |
| title | Adipose-derived stem cells attenuate rheumatoid arthritis by restoring CX3CR1+ synovial lining macrophage barrier |
| title_full | Adipose-derived stem cells attenuate rheumatoid arthritis by restoring CX3CR1+ synovial lining macrophage barrier |
| title_fullStr | Adipose-derived stem cells attenuate rheumatoid arthritis by restoring CX3CR1+ synovial lining macrophage barrier |
| title_full_unstemmed | Adipose-derived stem cells attenuate rheumatoid arthritis by restoring CX3CR1+ synovial lining macrophage barrier |
| title_short | Adipose-derived stem cells attenuate rheumatoid arthritis by restoring CX3CR1+ synovial lining macrophage barrier |
| title_sort | adipose derived stem cells attenuate rheumatoid arthritis by restoring cx3cr1 synovial lining macrophage barrier |
| topic | Mesenchymal stem cells Rheumatoid arthritis Macrophage Mitochondria |
| url | https://doi.org/10.1186/s13287-025-04144-5 |
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