Ectopic engraftment of nociceptive neurons derived from hPSCs for pain relief and joint homeostasis

SUMMARY Chronic pain arises from the interplay of inflammatory signals that activate and sensitize nociceptors within injured tissues. Most analgesics fail clinically due to their mono-targeted mechanisms. Here, we apply human pluripotent stem cell–derived nociceptive neurons (hPSC-NNs) as therapeutic agents for osteoarthritis, targeting both pain and joint degeneration. We generated sensory neurons from hPSCs and identified CD200 as a nociceptor marker. Transcriptomic and functional profiling revealed that CD200highhPSC-NNs closely resemble human nociceptors, expressing pain-relevant receptors and ion channels. Strikingly, ectopic transplantation of CD200highhPSC-NNs into the knee joint of osteoarthritic mice reduced pain and promoted bone and cartilage repair, whereas CD200low cells exhibited no benefit. Mechanistically, human and mouse proteomics suggest that CD200highhPSC-NNs act as decoys by sequestering inflammatory ligands while secreting reparative factors in joint tissues. These findings uncover a fundamental role of nociceptors in tissue repair, providing a multi-targeted, disease-modifying strategy for OA and chronic pain. HIGHLIGHTS hPSC-derived nociceptors (hPSC-NNs) as Decoy Engraftment for Cellular Interception and Repair (DECIR) when transplanted into the knee joint, extending beyond conventional regenerative strategies CD200 serves as a clinically actionable surface marker for the purification of hPSC-NNs Ectopic grafting of CD200high hPSC-NNs delivers dual benefits, alleviating pain and modulating the neuro-immune environment within joint tissues Proteomic analyses reveal that CD200highhPSC-NNs sequester inflammatory mediators and secrete reparative factors to support joint homeostasis Competing Interest Statement Z.W., G.L., and X.D. are the co-founders for SereNeuro Therapeutics.