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

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 <i>CD200</i> as a nociceptor marker. Transcriptomic and functional profiling revealed that <i>CD200</i> ^<i>high</i> hPSC-NNs closely resemble human nociceptors, expressing pain-relevant receptors and ion channels. Strikingly, ectopic transplantation of <i>CD200</i> ^<i>high</i> hPSC-NNs into the knee joint of osteoarthritic mice reduced pain and promoted bone and cartilage repair, whereas <i>CD200</i> ^<i>low</i> cells exhibited no benefit. Mechanistically, human and mouse proteomics suggest that <i>CD200</i> ^<i>high</i> hPSC-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.