Cerebral-Organoid-Derived Exosomes Alleviate Oxidative Stress and Promote LMX1A-Dependent Dopaminergic Differentiation.

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.

Metformin coordinates with mesenchymal cells to promote VEGF-mediated angiogenesis in diabetic wound healing through Akt/mTOR activation.

INTRODUCTION: Cell therapy with mesenchymal stem cells (MSCs) and biomaterials holds great potential for the treatment of diabetic ulceration; however, the underlying mechanism as well as its compatibility with the first-line anti-diabetic drug, metformin (MTF), has not been well elucidated. METHODS: MSCs derived from the umbilical cord were labeled with fluorescent proteins, followed by transplantation in a fibrin scaffold (MSCs/FG) onto the STZ-induced diabetic wound in a C57BL6/J mouse model. MTF was administered by oral gavage at a dose of 250 mg/kg/day. The wound healing rate, epithelization, angiogenesis, and underlying mechanism were evaluated in MSCs/FG- and MTF-treated diabetic wounds. Moreover, the dose-dependent effects of MTF and involvement of the Akt/mTOR pathway were analyzed in keratinocyte and fibroblast cultures. RESULTS: MSCs/FG significantly promoted angiogenesis in diabetic wound healing without signs of differentiation or integration. The recruitment of fibroblasts and keratinocytes by MSCs/FG promotes migration and vascular endothelial growth factor (VEGF) expression in an Akt/mTOR-dependent manner. MTF, which is generally considered a mTOR inhibitor, displayed dose-dependent effects on MSC-unregulated Akt/mTOR and VEGF expression. Oral administration of MTF at an anti-diabetic dosage synergistically acted with MSCs/FG to promote Akt/mTOR activation, VEGF expression, and subsequent angiogenesis in diabetic wounds; however, it reduced the survival of MSCs. CONCLUSIONS: Our study identifies that MTF coordinates with mesenchymal cells to promote Akt/mTOR activation and VEGF-mediated angiogenesis during diabetic wound healing. These findings offer new insights into MSCs engraftment in FG scaffolds for diabetic wound healing and provide support for the promotion of MSCs therapy in patients prescribed with MTF.

The Different Molecular Code in Generation of Dopaminergic Neurons from Astrocytes and Mesenchymal Stem Cells.

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.