Urine-derived stem cells (UdSCs) possess a remarkable anti-inflammatory and immune-modulating activity. However, the clinical significance of UdSCs in autoimmune inflammatory diseases such as rheumatoid arthritis (RA) is yet to be explored. Hence, we tested the UdSCs response to an articular RA microenvironment. To simulate the inflamed RA joint more authentically in vitro, we treated cells with rheumatoid synovial fluids (RASFs) collected from RA patients, serum deprivation, acidosis (pH 7.0 and 6.5), and their combinations. Firstly, the RASFs pro-inflammatory status was assessed by cytokine quantification. Then, UdSCs were exposed to the RA environmental factors for 48 h and cell proliferation, gene expression and secretion of immunomodulatory factors were evaluated. The immunosuppressive potential of pre-conditioned UdSCs was also assessed via co-cultivation with activated peripheral blood mononuclear cells (PBMCs). In all experimental conditions, UdSCs’ proliferation was not affected. Conversely, extracellular acidosis considerably impaired the viability/proliferation of adipose tissue-derived stem cells (ATSCs). In the majority of cases, exposure to RA components led to the upregulated expression of IL-6, TSG6, ICAM-1, VCAM-1, and PD-L1, all involved in immunomodulation. Upon RASFs and acidic stimulation, UdSCs secreted higher levels of immunomodulatory cytokines: IL-6, IL-8, MCP-1, RANTES, GM-CSF, and IL-4. Furthermore, RASFs and combined pretreatment with RASFs and acidosis promoted the UdSCs-mediated immunosuppression and the proliferation of activated PBMCs was significantly inhibited. Altogether, our data indicate that the RA microenvironment certainly has the capacity to enhance UdSCs’ immunomodulatory function. For potential preclinical/clinical applications, the intra-articular injection might be a reasonable approach to maximize UdSCs’ therapeutic efficiency in the RA treatment.

Tendon injuries affect millions of people globally and are among the most prevalent musculoskeletal conditions, frequently resulting in chronic pain, reduced mobility, and functional impairment. While conservative and surgical treatments are available, limitations such as low healing capacity, scar formation, and reduced biomechanics necessitate alternative approaches. Tissue engineering offers a promising solution by combining cells, scaffolds, and bioactive molecules to regenerate tendon tissue. This review presents key concepts and emerging trends, highlighting the cellular components, scaffold materials, and manufacturing processes. Tenocytes and mesenchymal stem cells are fundamental for tissue regeneration, as they synthesize extracellular matrix components and regulate inflammatory responses. Various natural and synthetic polymers have been fabricated into scaffolds that mimic the structure and biomechanics of natural tendons. Composite and hybrid scaffolds are utilized to improve the biocompatibility of natural materials with the mechanical stability of synthetic materials. Advanced technologies, such as electrospinning, freeze-drying, and 3D bioprinting, enable the creation of scaffolds with defined architecture and functional gradients, improving cell alignment, differentiation, and tendon–bone integration. Although promising preclinical data exists, major challenges remain in translating these strategies clinically, particularly vascularization, immune rejection, and mechanical stability. Continued interdisciplinary attempts in biomaterials science, cellular biology, and engineering are crucial to advancing clinically viable tendon tissue engineering.