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Metal-organic polyhedra maintain the self-renewal of embryonic stem cells
R. Wang et al.
Nature Communications 2025 Sep
Abstract
Embryonic stem cells (ESC) are pluripotent, with the potential to differentiate into multiple cell types, making them a valuable tool for regenerative medicine and disease therapy. However, common culture methods face challenges, including strict operating procedures and high costs. Currently, Leukemia inhibitory factor (LIF), an indispensable bioactive protein for ESC culture, is typically applied to maintain self-renewal and pluripotency, but its instability and high cost limit its effectiveness in stable culture conditions. Hence, we have developed an innovative strategy using a soluble nanomaterial, metal-organic polyhedra (MOPs), to effectively maintain the self-renewal and pluripotency of ESC. The selected amino-modified vanadium-based MOP not only exhibits excellent biocompatibility and high stability but also possesses similar or even superior biological functions compared to commercial LIF. Due to the precise structure of MOPs, the active site responsible for maintaining ESC pluripotency has been identified and regulated at the molecular level. The new ESC culture method significantly reduces costs, simplifies preparation, and enhances the practicality of biopharmaceutical preparation and storage. This represents the first case of using MOPs to maintain self-renewal of ECS, opening an avenue for introducing advanced materials into the development of innovative ESC culture methods. Subject terms: Biomaterials - cells, Chemical biology
Protective mechanisms against Alzheimer's disease in APOE3‐Christchurch homozygous astrocytes
X. Tian et al.
Alzheimer's & Dementia 2025 Sep
Abstract
Alzheimer's disease (AD) is characterized by tau pathology, leading to neurodegeneration. Astrocytes regulate central nervous system homeostasis and influence AD progression. The APOE3‐Christchurch (APOE3‐Ch) variant is linked to AD resilience, but its protective mechanisms remain unclear. Human induced pluripotent stem cell–derived astrocytes (APOE3‐Ch and wild type) were used to assess tau uptake, clearance, lipid metabolism, and transcriptomic adaptations. Fluorescently labeled 2N4R‐P301L tau oligomers were tracked, and pathway‐specific inhibitors dissected tau clearance mechanisms. Lipidomic and transcriptomic analyses were performed to identify genotype‐specific adaptations. APOE3‐Ch astrocytes exhibited enhanced tau uptake via heparan sulfate proteoglycan‐ and lipoprotein receptor‐related protein 1‐mediated pathways and superior clearance through lysosomal and proteasomal degradation. They exported less tau, limiting propagation. Transcriptomic analyses revealed upregulation of genes involved in cell projection assembly and endocytosis. Lipidomic profiling showed reduced ceramides and gamma‐linolenic acid, linked to decreased neuroinflammation and ferroptosis. APOE3‐Ch astrocytes promote tau clearance and metabolic adaptations, providing insights into genetic resilience in AD and potential therapeutic targets. APOE3‐Christchurch (APOE3‐Ch) astrocytes exhibit significantly increased tau internalization compared to wild‐type astrocytes, facilitated by upregulated heparan sulfate proteoglycan and low‐density lipoprotein receptor‐related protein 1 pathways. APOE3‐Ch astrocytes demonstrate more efficient tau degradation via both lysosomal and proteasomal pathways, while exporting significantly less tau, potentially reducing tau propagation in the central nervous system. APOE3‐Ch astrocytes show upregulation of genes involved in cell projection assembly and endocytosis, suggesting structural and functional modifications that enhance tau processing. Lipidomic profiling reveals reduced ceramide levels and gamma‐linolenic acid downregulation in APOE3‐Ch astrocytes, alterations linked to reduced neuroinflammatory and ferroptotic activity, contributing to the protective phenotype.
The Parkinson’s disease-associated LRRK2-G2019S variant restricts serine metabolism, leading to microglial inflammation and dopaminergic neuron degeneration
H. Kurniawan et al.
Journal of Neuroinflammation 2025 Oct
Abstract
A growing body of evidence implicates inflammation as a key hallmark in the pathophysiology of Parkinson’s disease (PD), with microglia playing a central role in mediating neuroinflammatory signaling in the brain. However, the molecular mechanisms linking microglial activation to dopaminergic neuron degeneration remain poorly understood. In this study, we investigated the contribution of the PD-associated LRRK2-G2019S mutation to microglial neurotoxicity using patient-derived induced pluripotent stem cell (iPSC) models. We found that LRRK2-G2019S mutant microglia exhibited elevated activation markers, enhanced phagocytic capacity, and increased secretion of pro-inflammatory cytokines such as TNF-α. These changes were associated with metabolic dysregulation, including upregulated glycolysis and impaired serine biosynthesis. In 3D midbrain organoids, these overactivated microglia resulted in dopaminergic neuron degeneration. Notably, treating LRRK2-G2019S microglia with oxamic acid, a glycolysis inhibitor, attenuated microglial inflammation and reduced neuronal loss. Our findings underscore the link between metabolic targeting in microglia and dopaminergic neuronal loss in LRRK2-G2019S mutation, and highlight a potential strategy that warrants further preclinical evaluation.
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