Transplantation of exogenous dopaminergic (DA) neurons is an alternative strategy to replenish DA neurons that have lost along the course of Parkinson’s disease (PD). From the perspective of ethical acceptation, the source limitations, and the intrinsic features of PD pathology, astrocytes (AS) and mesenchymal stem cells (MSCs) are the two promising candidates of DA induction. In the present study, we induced AS or MSCs primary culture by the combination of the classical transcription-factor cocktails Mash1, Lmx1a, and Nurr1 (MLN), the chemical cocktails (S/C/D), and the morphogens SHH, FGF8, and FGF2 (S/F8/F2); the efficiency of induction into DA neurons was further analyzed by using immunostaining against the DA neuronal markers. AS could be efficiently converted into the DA neurons in vitro by the transcriptional regulation of MLN, and the combination with S/C/D or S/F8/F2 further increased the conversion efficiency. In contrast, MSCs from umbilical cord (UC-MSCs) or adipose tissue (AD-MSCs) showed moderate TH immunoreactivity after the induction with S/F8/F2 instead of with MLN or S/C/D. Our data demonstrated that AS and MSCs held lineage-specific molecular codes on the induction into DA neurons and highlighted the unique superiority of AS in the potential of cell replacement therapy for PD.

Diabetes mellitus (DM) has reached pandemic prevalence, significantly impacting global health. Accumulating evidence has highlighted a bidirectional relationship between diabetes and depression, with blood–brain barrier (BBB) disruption playing a pivotal role in the pathogenesis of and therapeutic approaches to both disorders. Mesenchymal stem cells (MSCs) have emerged as a promising cell-based therapeutic strategy for DM; however, their potential to mitigate DM-associated emotional deficits remains unclear. This study investigates whether MSCs can restore BBB integrity and improve emotional deficits in a diabetic mouse model via matrix metalloprotein-9 (MMP-9) inhibition. We used biochemical, molecular, and behavioral analyses to assess BBB function, inflammation, and emotional behavior. Our results demonstrated that diabetic conditions induce BBB dysfunction, characterized by the MMP-9-mediated degradation of tight junction (TJ) proteins claudin-5 (Cldn5) and occludin (Ocln), alongside neuroinflammation and emotional impairments. Notably, MSC administration restored BBB integrity and attenuated neuroinflammation by suppressing MMP-9 activity and upregulating TJ proteins. Importantly, MSC treatment not only alleviated anxiety- and depressive-like behaviors but also enhanced glycemic control in DMmodels. These findings elucidate the mechanistic basis of MSC therapy for DM-related neuropsychiatric complications and, crucially, reveal its dual therapeutic efficacy in concurrently ameliorating both neuropsychiatric symptoms and metabolic dysfunction in DM models. This synergistic therapeutic effect provides a translational rationale for advancing MSC-based therapies into clinical applications.