HPSC-derived mesenchymal stromal cells ameliorate murine autistic-like phenotypes through activating oxytocinergic neurons.

Autism spectrum disorder (ASD) is a heritable neurodevelopmental disorder marked by social deficits, repetitive behaviors, and psychiatric comorbidities. Despite its rising global prevalence, effective treatments remain elusive. Mesenchymal stromal cells (MSCs) offer therapeutic promise for ASD, although their mechanisms are unclear. Here, we show that induced pluripotent stem cell (iPSC)-derived MSCs alleviate anxiety, grooming, and social impairments in Shank3B knockout mice, a monogenic ASD model. Intravenously infused MSCs localize to the neurohypophysis, interface with oxytocin (OT)-producing neuron axons, and activate OT+ neurons in the paraventricular nucleus (PVN). MSC treatment also reduces autistic-like phenotypes in BTBR T + Itpr3tf/J mice, a model of idiopathic ASD, in an OT+ neuron-dependent manner. Mechanistically, prostaglandin E2 (PGE2) secreted by MSCs instigates the activation of OT+ neuron, while suppression of PGE2 production via short hairpin RNA (shRNA)-mediated knockdown of PTGS1 and PTGES diminishes their therapeutic efficacy. These findings reveal a mechanism whereby MSCs modulate OT+ neuroendocrine circuits to improve ASD-related behaviors.