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Progress in Modeling Neural Tube Development and Defects by Organoid Reconstruction

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Neuroscience Bulletin 2022年第11期38卷 1409-1419页

作者： Peng Li Yongchang Chen State key laboratory of primate biomedical research and Institute of primate Translational Medicine Kunming University of Science and TechnologyKunming 650500China Yunnan Key Laboratory of Primate Biomedical Research Kunming 650500China

It is clear that organoids are useful for studying the structure as well as the functions of organs and tissues;they are able to simulate cell-to-cell interactions,symmetrical and asymmetric division,proliferation,and migration of different cell groups.Some progress has been made using brain organoids to elucidate the genetic basis of certain neurodevelopmental disorders.Such as Parkinson’s disease and Alzheimer’s disease.However,research on organoids in early neural development has received insufficient attention,especially that focusing on neural tube precursors.In this review,we focus on the recent research progress on neural tube organoids and discuss both their challenges and potential solutions.

关键词： Neural tube Organoid Neural tube defect

Neurogenesis in primates versus rodents and the value of non-human primate models

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National Science Review 2023年第11期10卷 61-83页

作者： Runrui Zhang Hongxin Quan Yinfeng Wang Fucheng Luo State key laboratory of primate biomedical research Institute of Primate Translational MedicineKunming University of Science and Technology Yunnan Key Laboratory of Primate Biomedical Research

Neurogenesis, the process of generating neurons from neural stem cells, occurs during both embryonic and adult stages, with each stage possessing distinct characteristics. Dysfunction in either stage can disrupt normal neural development, impair cognitive functions, and lead to various neurological disorders. Recent technological advancements in single-cell multiomics and gene-editing have facilitated investigations into primate neurogenesis. Here, we provide a comprehensive overview of neurogenesis across rodents,non-human primates, and humans, covering embryonic development to adulthood and focusing on the conservation and diversity among species. While non-human primates, especially monkeys, serve as valuable models with closer neural resemblance to humans, we highlight the potential impacts and limitations of non-human primate models on both physiological and pathological neurogenesis research.

关键词： rodent primate embryonic neurogenesis adult neurogenesis

Cell reprogramming therapy for Parkinson’s disease

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Neural Regeneration research 2024年第11期19卷 2444-2455页

作者： Wenjing Dong Shuyi Liu Shangang Li Zhengbo Wang State key laboratory of primate biomedical research Institute of Primate Translational MedicineKunming University of Science and TechnologyKunmingYunnan ProvinceChina Yunnan Key Laboratory of Primate Biomedical Research KunmingYunnan ProvinceChina

Parkinson’s disease is typically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta.Many studies have been performed based on the supplementation of lost dopaminergic neurons to treat Parkinson’s disease.The initial strategy for cell replacement therapy used human fetal ventral midbrain and human embryonic stem cells to treat Parkinson’s disease,which could substantially alleviate the symptoms of Parkinson’s disease in clinical practice.However,ethical issues and tumor formation were limitations of its clinical application.Induced pluripotent stem cells can be acquired without sacrificing human embryos,which eliminates the huge ethical barriers of human stem cell therapy.Another widely considered neuronal regeneration strategy is to directly reprogram fibroblasts and astrocytes into neurons,without the need for intermediate proliferation states,thus avoiding issues of immune rejection and tumor formation.Both induced pluripotent stem cells and direct reprogramming of lineage cells have shown promising results in the treatment of Parkinson’s disease.However,there are also ethical concerns and the risk of tumor formation that need to be addressed.This review highlights the current application status of cell reprogramming in the treatment of Parkinson’s disease,focusing on the use of induced pluripotent stem cells in cell replacement therapy,including preclinical animal models and progress in clinical research.The review also discusses the advancements in direct reprogramming of lineage cells in the treatment of Parkinson’s disease,as well as the controversy surrounding in vivo reprogramming.These findings suggest that cell reprogramming may hold great promise as a potential strategy for treating Parkinson’s disease.

关键词： animal models astrocytes autologous cell reprogramming cell therapy direct lineage reprogramming dopaminergic neurons induced pluripotent stem cells non-human primates Parkinson’s disease

Loss of SHROOM3 affects neuroepithelial cell shape through regulating cytoskeleton proteins in cynomolgus monkey organoids

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Zoological research 2024年第2期45卷 233-241页

作者： Peng Li Ting Zhang Ruo Wu Jun-Yu Zhang Yan Zhuo Shan-Gang Li Jiao-Jian Wang Wen-Ting Guo Zheng-Bo Wang Yong-Chang Chen State key laboratory of primate biomedical research Institute of Primate Translational MedicineKunming University of Science and TechnologyKunmingYunnan 650500China Yunnan Key Laboratory of Primate Biomedical Research KunmingYunnan 650500China

Neural tube defects(NTDs)are severe congenital neurodevelopmental disorders arising from incomplete neural tube closure.Although folate supplementation has been shown to mitigate the incidence of NTDs,some cases,often attributable to genetic factors,remain unpreventable.The SHROOM3 gene has been implicated in NTD cases that are unresponsive to folate supplementation;at present,however,the underlying mechanism remains unclear.Neural tube morphogenesis is a complex process involving the folding of the planar epithelium of the neural plate.To determine the role of SHROOM3 in early developmental morphogenesis,we established a neuroepithelial organoid culture system derived from cynomolgus monkeys to closely mimic the in vivo neural plate phase.Loss of SHROOM3 resulted in shorter neuroepithelial cells and smaller nuclei.These morphological changes were attributed to the insufficient recruitment of cytoskeletal proteins,namely fibrous actin(F-actin),myosin II,and phospho-myosin light chain(PMLC),to the apical side of the neuroepithelial cells.Notably,these defects were not rescued by folate supplementation.RNA sequencing revealed that differentially expressed genes were enriched in biological processes associated with cellular and organ morphogenesis.In summary,we established an authentic in vitro system to study NTDs and identified a novel mechanism for NTDs that are unresponsive to folate supplementation.

关键词： Neural tube defects SHROOM3 Neuroepithelial Organoids Cynomolgus monkey

primate stem cells: bridge the translation from basic research to clinic application

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Science China(Life Sciences) 2019年第1期62卷 12-21页

作者： Tianqing Li Zongyong Ai Weizhi Ji Yunnan Key Laboratory of Primate Biomedical Research Institute of Primate Translational Medicine Kunming University of Science and Technology

A growing body of literature has shown that stem cells are very effective for the treatment of degenerative diseases in rodents but these exciting results have not translated to clinical practice. The difference results from the divergence in genetic, metabolic, and physiological phenotypes between rodents and humans. The high degree of similarity between non-human primates(NHPs) and humans provides the most accurate models for preclinical studies of stem cell therapy. Using a NHP model to understand the following key issues, which cannot be addressed in humans or rodents, will be helpful for extending stem cell applications in the basic science and the clinic. These issues include pluripotency of primate stem cells, the safety and efficiency of stem cell therapy, and transplantation procedures of stem cells suitable for clinical translation. Here we review studies of the above issues in NHPs and current challenges of stem cell applications in both basic science and clinical therapies. We propose that the use of NHP models, in particular combining the serial production and transplantation procedures of stem cells is the most useful for preclinical studies designed to overcome these challenges.

关键词： non-human primate pluripotent stem cells monkey disease model stem cell therapy pluripotency state transition transplantation procedures

Efficient Modulation of Exon Skipping via Antisense Circular RNAs

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research 2023年第3期6卷 485-490页

作者： Shuaiwei Ren Mei Huang Raoxian Bai Lijiao Chen Jiao Yang Junyu Zhang Wenting Guo Weizhi Ji Yongchang Chen State key laboratory of primate biomedical research Institute of Primate Translational MedicineKunming University of Science and TechnologyKunming 650500China Yunnan Key Laboratory of Primate Biomedical Research Kunming 650500China

Splice-switching antisense oligonucleotides(ASOs)and engineered U7 small nuclear ribonucleoprotein(U7 Sm OPT)are the most commonly used methods for exon skipping.However,challenges remain,such as limited organ delivery and repeated dosing for ASOs and unknown risks of by-products produced by U7 Sm OPT.Here,we showed that antisense circular RNAs(AS-circRNAs)can effectively mediate exon skipping in both minigene and endogenous transcripts.We also showed a relatively higher exon skipping efficiency at the tested Dmd minigene than U7 Sm OPT.AS-circRNA specifically targets the precursor mRNA splicing without off-target effects.Moreover,AS-circRNAs with adeno-associated virus(AAV)delivery corrected the open reading frame and restored the dystrophin expression in a mouse model of Duchenne muscular dystrophy.In conclusion,we develop an alternative method for regulating RNA splicing,which might be served as a novel tool for genetic disease treatment.

关键词： endogenous dystrophy Duchenne

Multiplexed single-cell transcriptome analysis reveals molecular characteristics of monkey pluripotent stem cell lines

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2023年第5期24卷 418-429页

作者： Shuang LI Zhenzhen CHEN Chuanxin CHEN Yuyu NIU State key laboratory of primate biomedical research Institute of Primate Translational MedicineKunming University of Science and TechnologyKunming 650500China Faculty of Life Science and Technology Kunming University of Science and TechnologyKunming 650500China Yunnan Key Laboratory of Primate Biomedical Research Kunming 650500China Bioland laboratory Guangzhou 510005China Guangzhou laboratory Guangzhou 510005China

Efforts have been made to establish various human pluripotent stem cell lines.However,such methods have not yet been duplicated in non-human primate cells.Here,we introduce a multiplexed single-cell sequencing technique to profile the molecular features of monkey pluripotent stem cells in published culture conditions.The results demonstrate suboptimized maintenance of pluripotency and show that the selected signaling pathways for resetting human stem cells can also be interpreted for establishing monkey cell lines.Overall,this work legitimates the translation of novel human cell line culture conditions to monkey cells and provides guidance for exploring chemical cocktails for monkey stem cell line derivation.

关键词： Monkey pluripotent stem cell Multiplexed single-cell sequencing Naive pluripotency Extended pluripotent stem cells

Embryo-Engineered Nonhuman primate Models:Progress and Gap to Translational Medicine

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research 2021年第1期2021卷 1627-1639页

作者： Mei Huang Jiao Yang Peng Li Yongchang Chen Yunnan Key Laboratory of Primate Biomedical Research Institute of Primate Translational MedicineKunming University of Science and TechnologyKunming 650500China State key laboratory of primate biomedical research Kunming 650500China

Animal models of human diseases are vital in better understanding the mechanism of pathogenesis and essential for evaluating and validating potential therapeutic interventions.As close relatives of humans,nonhuman primates(NHPs)play an increasingly indispensable role in advancing translational medicine research.In this review,we summarized the progress of NHP models generated by embryo engineering,analyzed their unique advantages in mimicking clinical patients,and discussed the remaining gap between basic research of NHP models to translational medicine.

关键词： diseases Medicine translational

The interplay between H3K36 methylation and DNA methylation in cancer

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癌症生物学与医学:英文版 2023年第8期20卷 545-552页

作者： Jiameng Dan Zeling Du Jinghong Zhang Taiping Chen State key laboratory of primate biomedical research Institute of Primate Translational MedicineKunming University of Science and TechnologyKunming 650500China Yunnan Key Laboratory of Primate Biomedical Research Kunming 650500China Department of Epigenetics and Molecular Carcinogenesis The University of Texas MD Anderson Cancer CenterHouston 77030USA Programs in Genetics and Epigenetics The University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical SciencesHouston 77030USA

Cancer refers to a diverse collection of diseases characterized by several well-established hallmarks,including the abilities to sustain proliferative signaling,evade growth suppressors,activate invasion and metastasis,enable replicative immortality,induce angiogenesis,and resist cell death1.Historically,genetic alterations(deletions,point mutations,and translocations)were thought to be the basis for tumor formation via the inactivation of tumor suppressors and activation of oncogenes.

关键词： alterations invasion mortality