Rheumatoid arthritis (RA) is a chronic, systemic and progressive autoimmune
disease of connective tissues common in middle age. Dysregulation of the tissue
homeostasis involving inflammation is the hallmark of disease pathogenesis, inducing autoimmune insults that frequently
lead to permanent disability. Although the advent of immunosuppressive and anti-inflammatory drugs and, more recently,
pathogenic TNF-TNF-R axis-targeting biologics significantly delayed progressive joint destruction with significant reduction
of disability and physical improvement, a large proportion of RA patients failed to respond to the treatment. In this
regard, mesenchymal stem/stromal cells (MSC) are particularly attractive to the refractory patients to the pharmacologic
intervention for their immunosuppressive/anti-inflammatory capacity as well as tissue reparative and/or regenerative potential.
Local or systemic delivery of MSCs led to promising results in preclinical as well as in clinical studies of RA and
thus proposing that these cells can be further exploited for their therapeutic application in RA and other degenerative connective
tissue diseases. Mechanistically, paracrine factors appear to be the main contributors of MSC-mediated tissue regeneration
in a number of preclinical and clinical studies rather than direct tissue cell replacement. More recently, extracellular
vesicles (EVs) released from MSCs emerged as key paracrine messengers that can also participate in the healing
process through influencing the local microenvironment with anti-inflammatory effects. It is highly likely that the use
of these EVs becomes beneficial in the treatment of RA. Yet, identification of key components involved in the regenerative
process needs to be assessed for developing efficient MSC-based strategy of RA treatment.