Obesity hinders the efficacy of adipose-derived stem cells for knee osteoarthritis by reducing the proportion of DPP4+ stem cells. 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. Overall design: To compare the efficacy of adipose-derived stem cells (ASCs) from healthy and obese mice in the context of osteoarthritis. ASCs were obtained through collagenase digestion of subcutaneous adipose tissue from mice and were then subjected to single cell sequencing