Abstract
The pathogenesis of the autoimmune rheumatological diseases including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) is complex with the involvement of several immune cell populations spanning both innate and adaptive immunity including different T-lymphocyte subsets and monocyte/macrophage lineage cells. Despite therapeutic advances in RA and SLE, some patients have persistent and stubbornly refractory disease. Herein, we discuss stromal cells' dual role, including multipotent mesenchymal stromal cells (MSCs) also used to be known as mesenchymal stem cells as potential protagonists in RA and SLE pathology and as potential therapeutic vehicles. Joint MSCs from different niches may exhibit prominent pro-inflammatory effects in experimental RA models directly contributing to cartilage damage. These stromal cells may also be key regulators of the immune system in SLE. Despite these pro-inflammatory roles, MSCs may be immunomodulatory and have potential therapeutic value to modulate immune responses favorably in these autoimmune conditions. In this review, the complex role and interactions between MSCs and the haematopoietically derived immune cells in RA and SLE are discussed. The harnessing of MSC immunomodulatory effects by contact-dependent and independent mechanisms, including MSC secretome and extracellular vesicles, is discussed in relation to RA and SLE considering the stromal immune microenvironment in the diseased joints. Data from translational studies employing MSC infusion therapy against inflammation in other settings are contextualized relative to the rheumatological setting. Although safety and proof of concept studies exist in RA and SLE supporting experimental and laboratory data, robust phase 3 clinical trial data in therapy-resistant RA and SLE is still lacking.
Highlights
The original description of multipotent mesenchymal stromal cells, previously known as mesenchymal stem cells (MSCs) that represented tissue-resident clonogenic stromal cells with multilineage osteogenic, chondrogenic, adipogenic and potentially other stromal lineage differentiation capacities emphasized their role in skeletal structure and integrity [1, 2]
This study has reported for the first time a decrease in the blood levels of CD19+ B cells with a decreased expression of BLyS receptor 3 (BR3), transmembrane activator and CAML interactor (TACI), and B-cell maturation antigen (BCMA) receptors and blood BAFF and APRIL levels 12 months after the MSC infusion
These mechanisms include the production of soluble factors, cell-cell interactions, extracellular vesicles, and recently described apoptosis-mediated immunosuppression
Summary
The original description of multipotent mesenchymal stromal cells, previously known as mesenchymal stem cells (MSCs) that represented tissue-resident clonogenic stromal cells with multilineage osteogenic, chondrogenic, adipogenic and potentially other stromal lineage differentiation capacities emphasized their role in skeletal structure and integrity [1, 2]. This review will focus on the interesting crosstalk between MSCs and immune cells and how this crosstalk impacts inflammatory mediators in two autoimmune/inflammatory joint diseases that both exhibit joint predilections; rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) We focus on these diseases in the experimental model settings and on preliminary clinical trials data emerging in humans where proof of concept preclinical studies showing systemic MSC infusion may be associated with beneficial impacts. Consolidating this knowledge is essential to understand further the emerging field of MSC use for immune homeostasis restoration and to facilitate the development and optimization of therapeutic methods, for resistant rheumatologic autoimmune disease that is refractory to all existing therapies
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