Immunoregulatory orchestrations in osteoarthritis and mesenchymal stromal cells for therapy.

Osteoarthritis (OA) is characterized by the inability of stable and complex joint structures to function as they did, accompanied by inflammation, tissue changes, chronic pain, and neuropathic inflammation. In the past, the primary focus on the causes of joint dysfunction has been on mechanical stress leading to cartilage wear. Further researches emphasize the aging of cartilage and subchondral bone triggered cartilage lesion and osteophyte formation. Recently, the effects of immune cells, particularly macrophages and T cells, have been receiving focused attention. Herein, we primarily discuss the role of macrophages and T cells in the progression of OA and how mild inflammation in cartilage, subchondral bone, synovium, muscles, and nerves influences the progression of OA. Additionally, this review highlights the interaction between mesenchymal stromal cells (MSCs) and macrophages, as well as MSCs and T cells, along with how these interactions affect OA development and treatment. Finally, we explore future research directions and issues that still need to be addressed, providing more insights for the clinical translation of MSC-based therapy for OA. The translational potential of this article: This review highlights the promising translational potential of MSCs in OA therapy by targeting immunoregulatory networks. MSCs directly modulating macrophage M1/M2 polarization, Th1/Th2 and Th/Treg balance of T cells to suppress inflammation, thereby promoting cartilage repair and subchondral bone remodeling. Their ability to synergize with biomaterials or drug carriers enhances therapeutic precision and efficacy. However, challenges like MSCs survival in inflammatory microenvironments, heterogeneity in immune cell responses, and personalized treatment strategies require further optimization. Advances in genetical engineered strategies, extracellular vesicles, scaffolds/hydrogels or nanoparticle-based approaches may bridge these gaps, offering scalable solutions for clinical translation. This work underscores MSC-based therapies as a transformative approach for OA, pending refinement of delivery systems and patient stratification.