Improvement of Rheumatoid Arthritis Via MSCs-Exo in Combination With Rh2
Introduction
In light of a statistics report by World Health Organization (WHO), there are 18 million people suffering from rheumatoid arthritis (RA) worldwide in 2019, where the prevalence of female is 2.5 times that of male. This disorder greatly affects the life quality of patients and even causes disability in severe case. Noteworthily, mesenchymal stem cell-derived exosome (MSCs-exo) in combination with ginsenoside Rh2 has been unveiled to be effective in alleviating RA symptoms, holding a great promise as an adjuvant drug for RA.
About RA
RA represents a chronic autoimmune disease generally occurring in middle age, which is chiefly featured by vascular proliferation, synovium inflammation and the stiffness/swelling/deformation/pain of one or more joints. At present, the treatment of RA relies on corticosteroids, nonsteroidal anti-inflammatory drugs, synthetic disease-modifying anti-rheumatic drugs, and biological agents. Yet, long-term use of these drugs may be accompanied with various adverse effects such as infection, liver damage, gastrointestinal damage, and heart failure.
MSCs vs. MSCs-exo
MSCs, with multiple differentiation potential, can reduce joint inflammation in RA. Nevertheless, there are potential risks such as immunogenicity, heterogeneity of different batches of cells, tumorigenicity, and ethical issues, limiting the application of MSCs.
MSCs-exo is small extracellular vesicle secreted by MSCs, whose diameter ranges from 30 to 150 nanometers. It can carry biologically active substances such as nucleic acids and small molecules, fulfilling the function of MSCs. Relative to MSCs, MSCs-exo has low immunogenicity and has no risk of tumor formation and ethical constraints.
MSCs-exo is small extracellular vesicle secreted by MSCs, whose diameter ranges from 30 to 150 nanometers. It can carry biologically active substances such as nucleic acids and small molecules, fulfilling the function of MSCs. Relative to MSCs, MSCs-exo has low immunogenicity and has no risk of tumor formation and ethical constraints.
Research protocol
A collagen-induced arthritis (CIA) model is constructed in rats, followed by the treatment of phosphate-buffered saline or single/combined therapy of MSCs-exo and ginsenoside Rh2. The rat fences are collected for 16 rRNA amplification sequencing and untargeted metabolomics analysis.
Significant efficacy of MSCs-exo combined with ginsenoside Rh2 in RA
The combined therapy of MSCs-exo and ginsenoside Rh2, to a large extent, ameliorates RA symptoms in CIA model rats, as manifested by the reduction of joint swelling as well as significant decline in arthritis score and paw thickness.
Meanwhile, the histopathological changes in CIA model rats are apparently improved. Rh2 enhances the ability of MSC-exo to suppress the expression of inflammatory factors in synovium and cartilage of CIA model rats, as evidenced by the downregulation of TNF-α, IL-1β and IL-6 as well as upregulation of IL-10 in exo+Rh2 group. Besides, bone erosion in the ankle joints of CIA rats is improved, as attested by the obvious increases in BMD and Tb.Th, as well as prominent decreases in BS/BV and Tb.Sp in exo+Rh2 group.
Meanwhile, the histopathological changes in CIA model rats are apparently improved. Rh2 enhances the ability of MSC-exo to suppress the expression of inflammatory factors in synovium and cartilage of CIA model rats, as evidenced by the downregulation of TNF-α, IL-1β and IL-6 as well as upregulation of IL-10 in exo+Rh2 group. Besides, bone erosion in the ankle joints of CIA rats is improved, as attested by the obvious increases in BMD and Tb.Th, as well as prominent decreases in BS/BV and Tb.Sp in exo+Rh2 group.
Essential role of gut-joint axis in RA
Gut microbiota and metabolites have been deemed to be critical in developing RA. Strikingly, MSCs-exo and Rh2 can significantly ameliorate the disturbed gut microbiota in CIA model rats. The regulation of Candidatus_Saccharibacteria and Clostridium_XlVb may be the most pivotal. Concretely, Candidatus_Saccharibacteria modulates the metabolic pathway of vitamin digestion and absorption by pantothenic acid and vitamin D3 alterations. As for Clostridium_XlVb, it regulates 16(R)-HETE alterations in the arachidonic acid metabolic pathway.
Conclusion
MSCs-exo and Rh2 act synergistically to ameliorate RA by modulating the gut microbiota and metabolites, especially the reshaping of Candidatus_Saccharibacteria and Clostridium_XlVb abundance.
Reference
Zhou Z, Li Y, Wu S, et al. Host-microbiota interactions in collagen-induced arthritis rats treated with human umbilical cord mesenchymal stem cell exosome and ginsenoside Rh2. Biomed Pharmacother. Published online April 2, 2024. doi:10.1016/j.biopha.2024.116515
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