Functional Comparison of Synovial Membrane MSCs and iPSC-Derived iMSCs from Osteoarthritis-Diagnosed Patients

Osteoarthritis (OA) is a chronic disease characterized by progressive cartilage degeneration, subchondral bone changes, and synovitis, leading to joint dysfunction. Although stem cell-based therapies offer promise, synovial membrane-derived mesenchymal stem cells (SM-MSCs) from OA patients display donor-dependent declines in proliferative and chondrogenic potential, restricting their utility as a cell source for regenerative medicine strategies. Induced pluripotent stem cells (iPSCs) provide a platform for scalable and patient-specific regenerative applications but concerns regarding genetic instability and tumorigenicity persist. Reprogramming endogenous SM-MSCs into iPSCs and subsequent derivation of induced MSCs (iMSCs) may mitigate age- and disease-related epigenetic drift, enabling the generation of individualized, clinically relevant cell products for OA treatment. This study systematically compares the regenerative and chondrogenic attributes of patient-matched SM-MSCs and iMSCs generated via two integration-free iPSC reprogramming methods: Sendai virus (SeV) transduction and episomal nucleofection using core pluripotency transcription factors. SM-MSCs were isolated from two OA-diagnosed patients (a female and male donor). Genomic integrity of derived iPSC lines was confirmed via G-banded karyotyping, while transgene clearance and pluripotency were verified through flow cytometry, immunocytochemistry, qualitative PCR, and in vivo teratoma assays. iMSC identity was validated by flow cytometry and in vitro trilineage differentiation potential. Both reprogramming strategies yielded iPSC colonies; however, SeV-derived lines, particularly from the male donor, exhibited compromised stability and increased spontaneous differentiation, restricting their progression to iMSC derivation. Only episomal iPSC lines maintained robust pluripotency and supported iMSC generation for both donors. Comparative analyses included in vitro chondrogenesis, global proteomic profiling, and functional analysis using an in vivo post-traumatic OA mouse model to assess cartilage repair efficacy of the cell populations. This study highlights the therapeutic potential of iMSCs while analyzing donor effects, reprogramming method selection, and the need for molecular validation in developing effective OA regenerative therapies. It contributes to our understanding of patient-specific cell sources and integration-free cellular reprogramming for translational joint repair.