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 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 TMIC-56. ROLE OF HUMAN BRAIN TUMOR STEM CELLS-DERIVED EXTRACELLULAR VESICLES ON THE PHENOTYPIC TRANSDIFFERENTIATION OF HUMAN NEURAL PROGENITOR CELLS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi260-vi260
Author(s):  
Natanael Zarco ◽  
Emily Norton ◽  
Montserrat Lara-Velazquez ◽  
Anna Carrano ◽  
Alfredo Quinones-Hinojosa ◽  
...  
Keyword(s):  
Stem Cells ◽  
Brain Tumor ◽  
Tumor Microenvironment ◽  
Extracellular Vesicles ◽  
Primary Cultures ◽  
Adult Brain ◽  
Cell Subpopulation ◽  
Tumor Stem Cells ◽  
Brain Tumor Stem Cells

Abstract Glioblastoma (GBM) is the most aggressive of all the brain tumors with a median patient survival less than 15 months. Despite of surgical resection, radiotherapy, and chemotherapy, recurrence rate is almost 100%. A great percentage of GBM tumors (~60%) infiltrate and contact the ventricular-subventricular zone (V-SVZ). Interestingly, these tumors are the most aggressive, and invariably lead to higher distal recurrence rates, shorter time to tumor progression, and lower overall survival of the patient. The reason for this role of V-SVZ-proximity on the outcome of GBM patients is unknown. We suggest that a potential explanation is the interaction of GBM with the V-SVZ. This region is the largest neurogenic niche in the adult brain where neural stem cells (NSCs) give rise to newborn neuroblasts that migrate toward the olfactory bulb. In GBM there is a cell subpopulation called brain tumor stem cells (BTSCs) with NSCs-like characteristics, but with added potential for tumor initiation, recurrence and invasiveness. Tumor microenvironment plays an important role in migration and invasion process. In the present work, we used the total exosome isolation kit to purify Extracellular Vesicles (EVs) from human primary cultures of BTSCs. We determined that BTSCs-derived EVs contain specific information that is transfer to primary cultures of human Neural Progenitors Cells (NPCs) modulating their proliferation rate, cell viability, and migration. In addition, we identify that NPCs taken up BTSCs-derived EVs and significantly increase the expression levels of stemness-related genes such as Nestin, Nanog, and Sox2, suggesting that a phenotypic transdifferentiation is being carry out. These results support our hypothesis that GBM modulate the tumor microenvironment close to the V-SVZ by releasing EVs that target cellular components in this region and promote their phenotypic transformation, highlighting that NPCs biology changes in the context of tumor environment.

scholarly journals Notch1 down-regulation in lineage-restricted niches of mouse eccrine sweat glands

2021 ◽  
Author(s):  
Yuzhen Wang ◽  
Bin Yao ◽  
Xianlan Duan ◽  
Jianjun Li ◽  
Wei Song ◽  
...  
Keyword(s):  
Stem Cells ◽  
Gene Ontology ◽  
Enrichment Analysis ◽  
Differentially Expressed ◽  
Sweat Glands ◽  
Sequencing Analysis ◽  
Differentially Expressed Proteins ◽  
Epidermal Stem Cells ◽  
Eccrine Sweat Glands

Abstract BackgroundEccrine sweat gland (SG) restrictedly exists in mouse foot pads indicating that mouse plantar dermis (PD) contains the SG lineage-restricted niches. However, it is still unclear how niches can affect stem cell fates.MethodsIn this study, we tried to find the key cues by which stem cells sense and interact with the SG lineage-specific niches. Briefly, we used transcriptomics RNA sequencing analysis to screen differentially expressed genes between SG cells and epidermal stem cells (ES), and then we used proteomic analysis to screen differentially expressed proteins between PD and dorsal dermis (DD).ResultsWe found that Notch1 is not only closely related to embryonic SG morphogenesis based on Gene Ontology enrichment analysis but also differentially down-regulated during SG formation in the levels of genes and proteins. Furthermore, immunochemistry and immunofluorescence staining verified that Notch1 was continuously down-regulated along with the process of SG morphogenesis. Especially, Notch1 positive cells almost disappeared neither in the emerging SG buds or in the newly-formed glandular structures.ConclusionHence, we speculated that Notch1 possibly acts as the role of “gatekeeper” during embryonic SG development and is the promising key cue that regulates the interactions between stem cells and the SG lineage-specific niches. Our attempts highlighted the role of Notch1 during embryonic SG organogenesis.Trial registration Not applicable.

scholarly journals Extracellular Vesicles Do Not Mediate the Anti-Inflammatory Actions of Mouse-Derived Adipose Tissue Mesenchymal Stem Cells Secretome

2021 ◽  
Vol 22 (3) ◽  
pp. 1375
Author(s):  
María Carmen Carceller ◽  
María Isabel Guillén ◽  
María Luisa Gil ◽  
María José Alcaraz
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Adipose Tissue ◽  
Extracellular Vesicles ◽  
Nuclear Factor Κb ◽  
Peritoneal Macrophages ◽  
Toll Like Receptor 4 ◽  
Anti Inflammatory ◽  
Phagocytic Response

Adipose tissue represents an abundant source of mesenchymal stem cells (MSC) for therapeutic purposes. Previous studies have demonstrated the anti-inflammatory potential of adipose tissue-derived MSC (ASC). Extracellular vesicles (EV) present in the conditioned medium (CM) have been shown to mediate the cytoprotective effects of human ASC secretome. Nevertheless, the role of EV in the anti-inflammatory effects of mouse-derived ASC is not known. The current study has investigated the influence of mouse-derived ASC CM and its fractions on the response of mouse-derived peritoneal macrophages against lipopolysaccharide (LPS). CM and its soluble fraction reduced the release of pro-inflammatory cytokines, adenosine triphosphate and nitric oxide in stimulated cells. They also enhanced the migration of neutrophils or monocytes, in the absence or presence of LPS, respectively, which is likely related to the presence of chemokines, and reduced the phagocytic response. The anti-inflammatory effect of CM may be dependent on the regulation of toll-like receptor 4 expression and nuclear factor-κB activation. Our results demonstrate the anti-inflammatory effects of mouse-derived ASC secretome in mouse-derived peritoneal macrophages stimulated with LPS and show that they are not mediated by EV.

Extracellular vesicles, stem cells and the role of miRNAs in neurodegeneration

2021 ◽  
Vol 19 ◽  
Author(s):  
Ayaz M. Belkozhayev ◽  
Minnatallah Al-Yozbaki ◽  
Alex George ◽  
Raigul Ye Niyazova ◽  
Kamalidin O. Sharipov ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neurodegenerative Diseases ◽  
Extracellular Vesicles ◽  
Intercellular Communication ◽  
Direct Consequence ◽  
Therapeutic Benefit ◽  
The Body ◽  
A Cell ◽  
Crucial Information

There are different modalities of intercellular communication governed by cellular homeostasis. In this review, we will explore one of these forms of communication called extracellular vesicles (EVs). These vesicles are released by all cells in the body and are heterogeneous in nature. The primary function of EVs is to share information through their cargo consisting of proteins, lipids and nucleic acids (mRNA, miRNA, dsDNA etc.) with other cells, which have a direct consequence on their microenvironment. We will focus on the role of EVs of mesenchymal stem cells (MSCs) in the nervous system and how these participate in intercellular communication to maintain physiological function and provide neuroprotection. However, deregulation of this same communication system could play a role in several neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, multiple sclerosis, prion disease and Huntington’s disease. The release of EVs from a cell provides crucial information to what is happening inside the cell and thus could be used in diagnostics and therapy. We will discuss and explore new avenues for the clinical applications of using engineered MSC-EVs and their potential therapeutic benefit in treating neurodegenerative diseases.

scholarly journals Thrombin Preconditioning Boosts Biogenesis of Extracellular Vesicles from Mesenchymal Stem Cells and Enriches Their Cargo Contents via Protease-Activated Receptor-Mediated Signaling Pathways

2019 ◽  
Vol 20 (12) ◽  
pp. 2899 ◽  
Author(s):  
Dong Kyung Sung ◽  
Se In Sung ◽  
So Yoon Ahn ◽  
Yun Sil Chang ◽  
Won Soon Park
Keyword(s):  
Stem Cells ◽  
Signaling Pathways ◽  
Extracellular Vesicles ◽  
Akt Signaling ◽  
Human Umbilical Cord Blood ◽  
Human Umbilical Cord ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Specific Antagonist

We investigated the role of protease-activated receptor (PAR)-mediated signaling pathways in the biogenesis of human umbilical cord blood-derived mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) and the enrichment of their cargo content after thrombin preconditioning. Immunoblot analyses showed that MSCs expressed two PAR subtypes: PAR-1 and PAR-3. Thrombin preconditioning significantly accelerated MSC-derived EV biogenesis more than five-fold and enriched their cargo contents by more than two-fold via activation of Rab5, early endosomal antigen (EEA)-1, and the extracellular signal regulated kinase (ERK)1/2 and AKT signaling pathways. Blockage of PAR-1 with the PAR-1-specific antagonist, SCH79797, significantly suppressed the activation of Rab5, EEA-1, and the ERK1/2 and AKT pathways and subsequently increased EV production and enriched EV cargo contents. Combined blockage of PAR-1 and PAR-3 further and significantly inhibited the activation of Rab5, EEA-1, and the ERK1/2 and AKT pathways, accelerated EV production, and enriched EV cargo contents. In summary, thrombin preconditioning boosted the biogenesis of MSC-derived EVs and enriched their cargo contents largely via PAR-1-mediated pathways and partly via PAR-1-independent, PAR-3-mediated activation of Rab5, EEA-1, and the ERK1/2 and AKT signaling pathways.

The Distinct Role of Extracellular Vesicles Derived from Normal and Cancer Stem Cells

2017 ◽  
Vol 3 (3) ◽  
pp. 218-224 ◽  
Author(s):  
Cristina Grange ◽  
Marta Tapparo ◽  
Sharad Kholia ◽  
Benedetta Bussolati ◽  
Giovanni Camussi
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Extracellular Vesicles ◽  
Distinct Role

Role of cell cycle control in radiosensitization of mouse spermatogonial stem cells

2001 ◽  
Vol 77 (3) ◽  
pp. 357-363 ◽  
Author(s):  
P. P. W. Van Buul ◽  
A. Van Duyn-Goedhart ◽  
T. Beumer ◽  
A. L. Bootsma
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Cell Cycle Control ◽  
Spermatogonial Stem Cells

scholarly journals A Critical Role of TET1/2 Proteins in Cell-Cycle Progression of Trophoblast Stem Cells

2018 ◽  
Vol 10 (4) ◽  
pp. 1355-1368 ◽  
Author(s):  
Stephanie Chrysanthou ◽  
Claire E. Senner ◽  
Laura Woods ◽  
Elena Fineberg ◽  
Hanneke Okkenhaug ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Cell Cycle Progression ◽  
Critical Role ◽  
Cycle Progression ◽  
Trophoblast Stem Cells ◽  
Trophoblast Stem

scholarly journals Extracellular Vesicles: Evolving Factors in Stem Cell Biology

2016 ◽  
Vol 2016 ◽  
pp. 1-17 ◽  
Author(s):  
Muhammad Nawaz ◽  
Farah Fatima ◽  
Krishna C. Vallabhaneni ◽  
Patrice Penfornis ◽  
Hadi Valadi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Tumor Microenvironment ◽  
Extracellular Vesicles ◽  
Cell Biology ◽  
Trophic Factors ◽  
Stem Cell Biology ◽  
Cell Fates ◽  
Bidirectional Communication

Stem cells are proposed to continuously secrete trophic factors that potentially serve as mediators of autocrine and paracrine activities, associated with reprogramming of the tumor microenvironment, tissue regeneration, and repair. Hitherto, significant efforts have been made to understand the level of underlying paracrine activities influenced by stem cell secreted trophic factors, as little is known about these interactions. Recent findings, however, elucidate this role by reporting the effects of stem cell derived extracellular vesicles (EVs) that mimic the phenotypes of the cells from which they originate. Exchange of genetic information utilizing persistent bidirectional communication mediated by stem cell-EVs could regulate stemness, self-renewal, and differentiation in stem cells and their subpopulations. This review therefore discusses stem cell-EVs as evolving communication factors in stem cell biology, focusing on how they regulate cell fates by inducing persistent and prolonged genetic reprogramming of resident cells in a paracrine fashion. In addition, we address the role of stem cell-secreted vesicles in shaping the tumor microenvironment and immunomodulation and in their ability to stimulate endogenous repair processes during tissue damage. Collectively, these functions ensure an enormous potential for future therapies.

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