Establishment of human cerebral organoid systems to model early neural development and assess the central neurotoxicity of environmental toxins

Human brain development is a complex process,and animal models often have significant limitations.To address this,researchers have developed pluripotent stem cell-derived three-dimensional structures,known as brain-like organoids,to more accurately model early human brain development and disease.To enable more consistent and intuitive reproduction of early brain development,in this study,we incorporated forebrain organoid culture technology into the traditional unguided method of brain organoid culture.This involved embedding organoids in matrigel for only 7 days during the rapid expansion phase of the neural epithelium and then removing them from the matrigel for further cultivation,resulting in a new type of human brain organoid system.This cerebral organoid system replicated the temporospatial characteristics of early human brain development,including neuroepithelium derivation,neural progenitor cell production and maintenance,neuron differentiation and migration,and cortical layer patterning and formation,providing more consistent and reproducible organoids for developmental modeling and toxicology testing.As a proof of concept,we applied the heavy metal cadmium to this newly improved organoid system to test whether it could be used to evaluate the neurotoxicity of environmental toxins.Brain organoids exposed to cadmium for 7 or 14 days manifested severe damage and abnormalities in their neurodevelopmental patterns,including bursts of cortical cell death and premature differentiation.Cadmium exposure caused progressive depletion of neural progenitor cells and loss of organoid integrity,accompanied by compensatory cell proliferation at ectopic locations.The convenience,flexibility,and controllability of this newly developed organoid platform make it a powerful and affordable alternative to animal models for use in neurodevelopmental,neurological,and neurotoxicological studies.

c-Myc regulates neural stem cell quiescence and activation by coordinating the cell cycle and mitochondrial remodeling

Dear Editor,In the adult brain,the transition from neural stem cell(NSC)quiescence to activation is a focal regulatory point for neural regeneration and dysregulations in the transition lead to brain disorders.1,2 During this transition,both cell cycle states and metabolism including mitochondria undergo extensive reprogramming.A deep understanding of such comprehensive changes is a prerequisite for a holistic picture of physiology and may aid disease combats.

Glioma stem cells and neural stem cells respond differently to BMP4 signaling

Malignant glioma is a highly heterogeneous and invasive primary brain tumor characterized by high recurrence rates,resistance to combined therapy,and dismal prognosis.Glioma stem cells(GSCs)are likely responsible for tumor progression,resistance to therapy,recurrence,and poor prognosis owing to their high self-renewal and tumorigenic potential.As a family member of BMP signaling,bone morphogenetic protein4(BMP4)has been reported to induce the differentiation of GSCs and neural stem cells(NSCs).However,the molecular mechanisms underlying the BMP4-mediated effects in these two cell types are unclear.In this study,we treated hGSCs and hNSCs with BMP4 and com-pared the phenotypic and transcriptional changes between these two cell types.Phenotypically,we found that the growth of hGSCs was greatly inhibited by BMP4,but the same treatment only increased the cell size of hNSCs.While the RNA sequencing results showed that BMP4 treatment evoked significantly transcriptional changes in both hGSCs and hNSCs,the profiles of differentially expressed genes were distinct between the two groups.A gene set that specifically targeted the proliferation and differentiation of hGSCs but not hNSCs was enriched and then validated in hGSC culture.Our results suggested that hGSCs and hNSCs responded differently to BMP4 stimulation.Understanding and investigating different responses between hGSCs and hNSCs will benefit finding partner factors working together with BMP4 to further suppress GSCs proliferation and stemness without disturbing NSCs.

Interferon-beta inhibits human glioma stem cell growth by modulating immune response and cell cycle related signaling pathways

Malignant Glioma is characterized by strong self-renewal potential and immature differentiation potential.The main reason is that malignant glioma holds key cluster cells,glioma stem cells(GSCs).GSCs contribute to tumorigenesis,tumor progression,recurrence,and treatment resistance.Interferon-beta(IFN-β)is well known for its anti-proliferative efficacy in diverse cancers.IFN-βalso displayed potent antitumor effects in malignant glioma.IFN-βaffect both GSCs and Neural stem cells(NSCs)in the treatment of gliomas.However,the functional comparison,similar or different effects of IFN-βon GSCs and NSCs are rarely reported.Here,we studied the similarities and differences of the responses to IFN-βbetween human GSCs and normal NSCs.We found that IFN-βpreferentially inhibited GSCs over NSCs.The cell body and nucleus size of GSCs increased after IFN-βtreatment,and the genomic analysis revealed the enrichment of the upregulated immune response,cell adhesion genes and down regulated cell cycle,ribosome pathways.Several typical cyclin genes,including cyclin A2(CCNA2),cyclin B1(CCNB1),cyclin B2(CCNB2),and cyclin D1(CCND1),were significantly downregulated in GSCs after IFN-βstimulation.We also found that continuous IFN-βstimulation after passage further enhanced the inhibitory effect.Our study revealed how genetic diversity resulted in differential effects in response to IFN-βtreatment.These results may contribute to improve the applications of IFN-βin anti-cancer immunotherapy.In addition,these results may also help to design more effective pharmacological strategies to target cancer stem cells while protecting normal neural stem cells.

An in vitro cellular system modelling progressive human adipose-derived stem cell aging

Adipose-derived stem cells （ADSCs） assume essential roles intissue homeostasis and aging and have been explored as regenera-tive therapies for a broad range of diseases including physiologicaland pathological aging [1 ]. These multipotent cells are plastic, cap-able to differentiate and transdifferentiate to a range of cell types[2]. With aging, diseases and inundergo cellular senescence [3].vitro passing, ADSCs decline andFor therapies, typically cells fromyoung adults before 5-8 passages should be used, posing majorobstacles for conditions requiring much more cells [4].