Adipose-derived Stem Cells Attenuate Rheumatoid Arthritis by Restoring CXCR1 Synovial Lining Macrophage Barrier

Overview

Journal Stem Cell Res Ther

Publisher Biomed Central

Date 2025 Mar 5

PMID 40038808

Authors

Lei Wang

Ming Hao

Yongyue Xu

Zhaoyan Wang

Hanqi Xie

Bo Zhang

Xue Zhang

Jun Lin

Xiaodan Sun

Jianbin Wang

Qiong Wu

Affiliations

Soon will be listed here.

Abstract

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease and the integrity of CXCR1 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 CXCR1 macrophages, require further investigation.

Methods: To explore the interaction between ADSCs and CXCR1 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 CXCR1 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 CXCR1 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 Atf3 Ccl3 subset of CXCR1 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 CXCR1 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 CXCR1 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.

References

Alivernini S, MacDonald L, Elmesmari A, Finlay S, Tolusso B, Gigante M . Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis. Nat Med. 2020; 26(8):1295-1306. DOI: 10.1038/s41591-020-0939-8. View

Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z . clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation (Camb). 2021; 2(3):100141. PMC: 8454663. DOI: 10.1016/j.xinn.2021.100141. View

Zhang Y, Pizzute T, Pei M . Anti-inflammatory strategies in cartilage repair. Tissue Eng Part B Rev. 2014; 20(6):655-68. PMC: 4241874. DOI: 10.1089/ten.TEB.2014.0014. View

Gu Z, Gu L, Eils R, Schlesner M, Brors B . circlize Implements and enhances circular visualization in R. Bioinformatics. 2014; 30(19):2811-2. DOI: 10.1093/bioinformatics/btu393. View

Culemann S, Gruneboom A, Nicolas-Avila J, Weidner D, Lammle K, Rothe T . Locally renewing resident synovial macrophages provide a protective barrier for the joint. Nature. 2019; 572(7771):670-675. PMC: 6805223. DOI: 10.1038/s41586-019-1471-1. View

Spees J, Olson S, Whitney M, Prockop D . Mitochondrial transfer between cells can rescue aerobic respiration. Proc Natl Acad Sci U S A. 2006; 103(5):1283-8. PMC: 1345715. DOI: 10.1073/pnas.0510511103. View

Fraenkel L, Bathon J, England B, St Clair E, Arayssi T, Carandang K . 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol. 2021; 73(7):1108-1123. DOI: 10.1002/art.41752. View

Dang C, ODonnell K, Zeller K, Nguyen T, Osthus R, Li F . The c-Myc target gene network. Semin Cancer Biol. 2006; 16(4):253-64. DOI: 10.1016/j.semcancer.2006.07.014. View

Jackson M, Morrison T, Doherty D, McAuley D, Matthay M, Kissenpfennig A . Mitochondrial Transfer via Tunneling Nanotubes is an Important Mechanism by Which Mesenchymal Stem Cells Enhance Macrophage Phagocytosis in the In Vitro and In Vivo Models of ARDS. Stem Cells. 2016; 34(8):2210-23. PMC: 4982045. DOI: 10.1002/stem.2372. View

10.

Barrilleaux B, Fischer-Valuck B, Gilliam J, Phinney D, OConnor K . Activation of CD74 inhibits migration of human mesenchymal stem cells. In Vitro Cell Dev Biol Anim. 2010; 46(6):566-72. DOI: 10.1007/s11626-010-9279-1. View

11.

Picelli S, Faridani O, Bjorklund A, Winberg G, Sagasser S, Sandberg R . Full-length RNA-seq from single cells using Smart-seq2. Nat Protoc. 2014; 9(1):171-81. DOI: 10.1038/nprot.2014.006. View

12.

Lopez-Santalla M, Fernandez-Perez R, Garin M . Mesenchymal Stem/Stromal Cells for Rheumatoid Arthritis Treatment: An Update on Clinical Applications. Cells. 2020; 9(8). PMC: 7465092. DOI: 10.3390/cells9081852. View

13.

Lopez-Santalla M, Conde C, Rodriguez-Trillo A, Garin M . Assessment of mesenchymal stem/stromal cell-based therapy in K/BxN serum transfer-induced arthritis. Front Immunol. 2022; 13:943293. PMC: 9589432. DOI: 10.3389/fimmu.2022.943293. View

14.

Yoshitomi H . Regulation of Immune Responses and Chronic Inflammation by Fibroblast-Like Synoviocytes. Front Immunol. 2019; 10:1395. PMC: 6593115. DOI: 10.3389/fimmu.2019.01395. View

15.

Boutet M, Courties G, Nerviani A, Le Goff B, Apparailly F, Pitzalis C . Novel insights into macrophage diversity in rheumatoid arthritis synovium. Autoimmun Rev. 2021; 20(3):102758. DOI: 10.1016/j.autrev.2021.102758. View

16.

Kanai R, Nakashima A, Doi S, Kimura T, Yoshida K, Maeda S . Interferon-γ enhances the therapeutic effect of mesenchymal stem cells on experimental renal fibrosis. Sci Rep. 2021; 11(1):850. PMC: 7807061. DOI: 10.1038/s41598-020-79664-6. View

17.

Kouskoff V, Korganow A, Duchatelle V, Degott C, Benoist C, Mathis D . Organ-specific disease provoked by systemic autoimmunity. Cell. 1996; 87(5):811-22. DOI: 10.1016/s0092-8674(00)81989-3. View

18.

Chernyavskij D, Galkin I, Pavlyuchenkova A, Fedorov A, Chelombitko M . [Role of Mitochondria in Intestinal Epithelial Barrier Dysfunction in Inflammatory Bowel Disease]. Mol Biol (Mosk). 2023; 57(6):1028-1042. DOI: 10.31857/S0026898423060058, EDN: QZKAEA. View

19.

Heinrich F, Lehmbecker A, Raddatz B, Kegler K, Tipold A, Stein V . Morphologic, phenotypic, and transcriptomic characterization of classically and alternatively activated canine blood-derived macrophages in vitro. PLoS One. 2017; 12(8):e0183572. PMC: 5560737. DOI: 10.1371/journal.pone.0183572. View

20.

Love M, Huber W, Anders S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15(12):550. PMC: 4302049. DOI: 10.1186/s13059-014-0550-8. View