Obesity hinders the efficacy of adipose-derived stem cells for knee osteoarthritis by reducing the proportion of DPP4+ stem cells.

Osteoarthritis (OA) is the most prevalent and disabling joint disease, while adipose-derived stem cells (ASCs) have emerged as a promising therapeutic option in pre-clinical studies. However, the therapeutic efficacy of ASCs may be influenced by the source of these cells, especially in obese patients. This study compared the effects of intra-articular injections of ASCs from wild-type (WT) and ob/ob (OB) mice. Behavioral and histological analyses demonstrated that WT-ASCs significantly alleviated OA symptoms, restoring paw withdrawal thresholds and improving gait parameters while reducing cartilage degradation. In contrast, OB-ASCs only partially improved gait and did not significantly affect cartilage degeneration. Single-cell RNA sequencing of stromal vascular fractions from subcutaneous adipose tissue revealed distinct ASC subpopulations, with DPP4+ cells being notably reduced in obese mice. In vitro, OB-ASCs and high-fat-diet (HFD)-ASCs exhibited impaired proliferation and chondrogenesis but HFD-ASCs retained anti-inflammatory properties. Further investigation using fluorescence-activated cell sorting (FACS) isolated DPP4+ and DPP4- ASCs from WT mice, demonstrating that DPP4+cells had superior chondrogenic potential and reduced OA pain more effectively than DPP4- cells. These findings suggest that obesity impairs the therapeutic potential of ASCs in OA, primarily due to reduced proliferation and chondrogenesis, and highlight DPP4+ ASCs as a promising candidate for cell therapy in OA.