Yuhan Duan

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.

MiRNAs have been shown to be involved in the regulation of a variety of physiological and pathological processes, but their use in the treatment of diseases is still limited due to their instability. Biomimetic nanomaterials combine nanomaterials with cellular components that are readily modifiable and biocompatible, making them an emerging miRNA delivery vehicle. In this study, adipose-derived MSC membranes were wrapped around PLGA-PEI loaded with miR-21 through co-extrusion and later transplanted into C57BL/6 mice wounds. The wound-healing rate, epithelialization, angiogenesis, and collagen deposition were assessed after treatment and corroborated in vitro. Our study demonstrated that m/NP/miR-21 can promote wound healing in terms of epithelialization, dermal reconstruction, and neovascularization, and it can regulate the corresponding functions of keratinocytes, fibroblasts, and vascular endothelial cells. m/NP/miR-21 can inhibit the expression of PTEN, a gene downstream of miR-21, and increase the phosphorylation activation of AKT, which can then regulate the functions of fibroblasts. In conclusion, this provides a new approach to therapy for skin wounds using microRNA transporters and biomimetic nanoparticles.

The remarkable advancements related to cerebral organoids have provided unprecedented opportunities to model human brain development and diseases. However, despite their potential significance in neurodegenerative diseases such as Parkinson’s disease (PD), the role of exosomes from cerebral organoids (OExo) has been largely unknown. In this study, we compared the effects of OExo to those of mesenchymal stem cell (MSC)-derived exosomes (CExo) and found that OExo shared similar neuroprotective effects to CExo. Our findings showed that OExo mitigated H₂O₂-induced oxidative stress and apoptosis in rat midbrain astrocytes by reducing excess ROS production, antioxidant depletion, lipid peroxidation, mitochondrial dysfunction, and the expression of pro-apoptotic genes. Notably, OExo demonstrated superiority over CExo in promoting the differentiation of human-induced pluripotent stem cells (iPSCs) into dopaminergic (DA) neurons. This was attributed to the higher abundance of neurotrophic factors, including neurotrophin-4 (NT-4) and glial-cell-derived neurotrophic factor (GDNF), in OExo, which facilitated the iPSCs’ differentiation into DA neurons in an LIM homeobox transcription factor 1 alpha (LMX1A)-dependent manner. Our study provides novel insight into the biological properties of cerebral organoids and highlights the potential of OExo in the treatment of neurodegenerative diseases such as PD.