scholarly journals Novel roles of small extracellular vesicles in regulating the quiescence and proliferation of neural stem cells

2021 ◽  
Author(s):  
Jingtian Zhang ◽  
Junki Uchiyama ◽  
Koshi Imami ◽  
Yasushi Ishihama ◽  
Ryoichiro Kageyama ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Neural Stem Cells ◽  
Extracellular Vesicles ◽  
Protein Translation ◽  
Adult Brain ◽  
Cell Cycle Protein ◽  
Complex Processes ◽  
G0 Phase ◽  
Cycle Regulation

Neural stem cells (NSCs) quiescence plays pivotal roles in securing sustainable neurogenesis and avoiding stemness exhaustion in the adult brain. The maintenance of quiescence and transition between proliferation and quiescence are complex processes associated with multiple niche signals, and environmental stimuli. Though the mechanisms of the transitions between NSC states have been extensively investigated, they remain to be fully elucidated. Exosomes are small extracellular vesicles (sEVs) containing functional units such as proteins, microRNAs, and mRNAs. It has already been demonstrated that sEVs actively participate in cancer cell proliferation and metastasis. However, the role of sEVs in NSC quiescence has not been investigated. Here, we applied proteomics to analyze the protein cargos of sEVs derived from proliferating, quiescent, and reactivating NSCs. Our findings revealed expression level fluctuations of NSCs sEV protein cargo at different proliferative conditions. We also identified functional clusters of gene ontology annotations from differentially expressed proteins in three sources of exosomes. Moreover, the use of exosome inhibitors revealed the contribution of exosomes to NSC quiescence at the entrance into quiescence, as well as in quiescence maintenance. Exosome inhibition delayed the entrance into quiescence by proliferating NSCs and allowed quiescent NSCs to exit from the G0 phase of the cell cycle. Protein translation was significantly upregulated in both quiescent NSCs and quiescent-induced NSCs via the exosome inhibition. Our results demonstrated that NSC exosomes are involved in regulating the quiescence of NSCs and provide a functional prediction of NSCs exosome protein cargos in terms of cell-cycle regulation and protein synthesis.

scholarly journals Novel Roles of Small Extracellular Vesicles in Regulating the Quiescence and Proliferation of Neural Stem Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Jingtian Zhang ◽  
Junki Uchiyama ◽  
Koshi Imami ◽  
Yasushi Ishihama ◽  
Ryoichiro Kageyama ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Gene Ontology ◽  
Extracellular Vesicles ◽  
Protein Translation ◽  
Adult Brain ◽  
Differentially Expressed Proteins ◽  
Complex Processes ◽  
G0 Phase

Neural stem cell (NSC) quiescence plays pivotal roles in avoiding exhaustion of NSCs and securing sustainable neurogenesis in the adult brain. The maintenance of quiescence and transition between proliferation and quiescence are complex processes associated with multiple niche signals and environmental stimuli. Exosomes are small extracellular vesicles (sEVs) containing functional cargos such as proteins, microRNAs, and mRNAs. The role of sEVs in NSC quiescence has not been fully investigated. Here, we applied proteomics to analyze the protein cargos of sEVs derived from proliferating, quiescent, and reactivating NSCs. Our findings revealed fluctuation of expression levels and functional clusters of gene ontology annotations of differentially expressed proteins especially in protein translation and vesicular transport among three sources of exosomes. Moreover, the use of exosome inhibitors revealed exosome contribution to entrance into as well as maintenance of quiescence. Exosome inhibition delayed entrance into quiescence, induced quiescent NSCs to exit from the G0 phase of the cell cycle, and significantly upregulated protein translation in quiescent NSCs. Our results suggest that NSC exosomes are involved in attenuating protein synthesis and thereby regulating the quiescence of NSCs.

scholarly journals Neural stem cells: involvement in adult neurogenesis and CNS repair

2008 ◽  
Vol 363 (1500) ◽  
pp. 2111-2122 ◽  
Author(s):  
Hideyuki Okano ◽  
Kazunobu Sawamoto
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Cell Transplantation ◽  
Adult Neurogenesis ◽  
Embryonic Stem ◽  
Adult Brain ◽  
Therapeutic Interventions ◽  
Cell Transplantation Therapy ◽  
Transplantation Therapy

Recent advances in stem cell research, including the selective expansion of neural stem cells (NSCs) in vitro , the induction of particular neural cells from embryonic stem cells in vitro , the identification of NSCs or NSC-like cells in the adult brain and the detection of neurogenesis in the adult brain (adult neurogenesis), have laid the groundwork for the development of novel therapies aimed at inducing regeneration in the damaged central nervous system (CNS). There are two major strategies for inducing regeneration in the damaged CNS: (i) activation of the endogenous regenerative capacity and (ii) cell transplantation therapy. In this review, we summarize the recent findings from our group and others on NSCs, with respect to their role in insult-induced neurogenesis (activation of adult NSCs, proliferation of transit-amplifying cells, migration of neuroblasts and survival and maturation of the newborn neurons), and implications for therapeutic interventions, together with tactics for using cell transplantation therapy to treat the damaged CNS.

scholarly journals Live-cell time-lapse imaging and single-cell tracking of in vitro cultured neural stem cells – Tools for analyzing dynamics of cell cycle, migration, and lineage selection

Methods ◽  
2018 ◽  
Vol 133 ◽  
pp. 81-90 ◽  
Author(s):  
Katja M. Piltti ◽  
Brian J. Cummings ◽  
Krystal Carta ◽  
Ayla Manughian-Peter ◽  
Colleen L. Worne ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Neural Stem Cells ◽  
Single Cell ◽  
Cell Tracking ◽  
Time Lapse ◽  
Live Cell ◽  
Time Lapse Imaging

scholarly journals Single cell 3’UTR analysis identifies changes in alternative polyadenylation throughout neuronal differentiation and in autism

2020 ◽  
Author(s):  
Manuel Göpferich ◽  
Nikhil Oommen George ◽  
Ana Domingo Muelas ◽  
Alex Bizyn ◽  
Rosa Pascual ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Neural Stem Cells ◽  
Single Cell ◽  
Neuronal Differentiation ◽  
Mrna Translation ◽  
Autism Spectrum ◽  
Adult Brain ◽  
Control Of Gene Expression ◽  
Risk Genes

SUMMARYAutism spectrum disorder (ASD) is a neurodevelopmental disease affecting social behavior. Many of the high-confident ASD risk genes relate to mRNA translation. Specifically, many of these genes are involved in regulation of gene expression for subcellular compartmentalization of proteins1. Cis-regulatory motifs that often localize to 3’- and 5’-untranslated regions (UTRs) offer an additional path for posttranscriptional control of gene expression. Alternative cleavage and polyadenylation (APA) affect 3’UTR length thereby influencing the presence or absence of regulatory elements. However, APA has not yet been addressed in the context of neurodevelopmental disorders. Here we used single cell 3’end sequencing to examine changes in 3’UTRs along the differentiation from neural stem cells (NSCs) to neuroblasts within the adult brain. We identified many APA events in genes involved in neurodevelopment, many of them being high confidence ASD risk genes. Further, analysis of 3’UTR lengths in single cells from ASD and healthy individuals detected longer 3’UTRs in ASD patients. Motif analysis of modulated 3’UTRs in the mouse adult neurogenic lineage and ASD-patients revealed enrichment of the cytoplasmic and polyadenylation element (CPE). This motif is bound by CPE binding protein 4 (CPEB4). In human and mouse data sets we observed co-regulation of CPEB4 and the CPEB-binding synaptic adhesion molecule amyloid beta precursor-like protein 1 (APLP1). We show that mice deficient in APLP1 show aberrant regulation of APA, decreased number of neural stem cells, and autistic-like traits. Our findings indicate that APA is used for control of gene expression along neuronal differentiation and is altered in ASD patients.

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