hUC-MSCs alleviate the symptoms of Parkinson's disease: Safety and efficacy studies in an open-label clinical trial and a mouse model, and multi-omics-based mechanistic analyses

Mesenchymal stem cell replacement therapy represents a promising therapeutic strategy for Parkinson's disease (PD), but the key cytokines involved in symptom relief are unknown. This study was designed as a single-arm, open-label exploratory clinical trial (ChiCTR2400086970) and enrolled 35 PD patients with an average age of 67.54 ± 8.29 years, disease duration of 6.97 ± 4.88 years, and an average UPDRS score of 84.57 ± 25.31. Following human umbilical cord mesenchymal stem cell (hUC-MSC) treatment, significant symptom improvement was observed in all patients. Neuromelanin levels in the substantia nigra increased, and cerebrospinal fluid analysis revealed a significant elevation in docosatetraenoyl ethanolamide (DEA) during the symptom remission period. Mechanistic studies based on PD mouse model demonstrated that hUC-MSCs exposed to cerebrospinal fluid up-regulated NCS1 expression, which targeted intermediate selective nerve cells and oligodendrocytes, activated endocannabinoid pathways, promoted DEA synthesis, regulated calcium metabolism, supported glutaminergic nerve cell proliferation, and enhanced NRG signaling between astrocytes and glutaminergic neurons. Our findings suggest that hUC-MSC infusion is safe and is associated with clinically meaningful improvements in PD patients, warranting further confirmation in randomized controlled trials.