scholarly journals Enhanced lysosomal degradation maintains the quiescent state of neural stem cells

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Taeko Kobayashi ◽  
Wenhui Piao ◽  
Toshiya Takamura ◽  
Hiroshi Kori ◽  
Hitoshi Miyachi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Membrane Trafficking ◽  
Egf Receptor ◽  
Membrane Receptors ◽  
Adult Brain ◽  
Conditional Knockout ◽  
Quiescent State ◽  
Lysosomal Degradation

AbstractQuiescence is important for sustaining neural stem cells (NSCs) in the adult brain over the lifespan. Lysosomes are digestive organelles that degrade membrane receptors after they undergo endolysosomal membrane trafficking. Enlarged lysosomes are present in quiescent NSCs (qNSCs) in the subventricular zone of the mouse brain, but it remains largely unknown how lysosomal function is involved in the quiescence. Here we show that qNSCs exhibit higher lysosomal activity and degrade activated EGF receptor by endolysosomal degradation more rapidly than proliferating NSCs. Chemical inhibition of lysosomal degradation in qNSCs prevents degradation of signaling receptors resulting in exit from quiescence. Furthermore, conditional knockout of TFEB, a lysosomal master regulator, delays NSCs quiescence in vitro and increases NSC proliferation in the dentate gyrus of mice. Taken together, our results demonstrate that enhanced lysosomal degradation is an important regulator of qNSC maintenance.

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 Sonic Hedgehog Signaling Mediates Resveratrol to Increase Proliferation of Neural Stem Cells After Oxygen-Glucose Deprivation/Reoxygenation Injury in Vitro

2015 ◽  
Vol 35 (5) ◽  
pp. 2019-2032 ◽  
Author(s):  
Wei Cheng ◽  
Pingping Yu ◽  
Li Wang ◽  
Changbo Shen ◽  
Xiaosong Song ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Sonic Hedgehog ◽  
Glucose Deprivation ◽  
Adult Brain ◽  
Immunocytochemical Staining ◽  
Oxygen Glucose Deprivation ◽  
Shh Signaling ◽  
Gli 1

Background/Aims: There is interest in drugs and rehabilitation methods to enhance neurogenesis and improve neurological function after brain injury or degeneration. Resveratrol may enhance hippocampal neurogenesis and improve hippocampal atrophy in chronic fatigue mice and prenatally stressed rats. However, its effect and mechanism of neurogenesis after stroke is less well understood. Sonic hedgehog (Shh) signaling is crucial for neurogenesis in the embryonic and adult brain, but relatively little is known about the role of Shh signaling in resveratrol-enhanced neurogenesis after stroke. Methods: Neural stem cells (NSCs) before oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro were pretreated with resveratrol with or without cyclopamine. Survival and proliferation of NSCs was assessed by the CCK8 assay and BrdU immunocytochemical staining. The expressions and activity of signaling proteins and mRNAs were detected by immunocytochemistry, Western blotting, and RT-PCR analysis. Results: Resveratrol significantly increased NSCs survival and proliferation in a concentration-dependent manner after OGD/R injury in vitro. At the same time, the expression of Patched-1, Smoothened (Smo), and Gli-1 proteins and mRNAs was upregulated, and Gli-1 entered the nucleus, which was inhibited by cyclopamine, a Smo inhibitor. Conclusion: Shh signaling mediates resveratrol to increase NSCs proliferation after OGD/R injury in vitro.

Dynamic effects of Fto in regulating the proliferation and differentiation of adult neural stem cells of mice

2019 ◽  
Vol 29 (5) ◽  
pp. 727-735 ◽  
Author(s):  
Yuhang Cao ◽  
Yingliang Zhuang ◽  
Junchen Chen ◽  
Weize Xu ◽  
Yikai Shou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Neuronal Development ◽  
Conditional Knockout ◽  
Biological Processes ◽  
Adult Neural Stem Cells ◽  
Proliferation And Differentiation

Abstract N 6-methyladenosine (m6A) modification of RNA is deposited by the methyltransferase complex consisting of Mettl3 and Mettl14 and erased by demethylase Fto and Alkbh5 and is involved in diverse biological processes. However, it remains largely unknown the specific function and mechanism of Fto in regulating adult neural stem cells (aNSCs). In the present study, utilizing a conditional knockout (cKO) mouse model, we show that the specific ablation of Fto in aNSCs transiently increases the proliferation of aNSCs and promotes neuronal differentiation both in vitro and in vivo, but in a long term, the specific ablation of Fto inhibits adult neurogenesis and neuronal development. Mechanistically, Fto deficiency results in a significant increase in m6A modification in Pdgfra and Socs5. The increased expression of Pdgfra and decreased expression of Socs5 synergistically promote the phosphorylation of Stat3. The modulation of Pdgfra and Socs5 can rescue the neurogenic deficits induced by Fto depletion. Our results together reveal an important function of Fto in regulating aNSCs through modulating Pdgfra/Socs5-Stat3 pathway.

scholarly journals LRIG1 is a gatekeeper to exit from quiescence in adult neural stem cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
María Ángeles Marqués-Torrejón ◽  
Charles A. C. Williams ◽  
Benjamin Southgate ◽  
Neza Alfazema ◽  
Melanie P. Clements ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Neural Stem Cells ◽  
Single Cell Analysis ◽  
Interferon Response ◽  
Quiescent State ◽  
Adult Neural Stem Cells ◽  
Protein Levels

AbstractAdult neural stem cells (NSCs) must tightly regulate quiescence and proliferation. Single-cell analysis has suggested a continuum of cell states as NSCs exit quiescence. Here we capture and characterize in vitro primed quiescent NSCs and identify LRIG1 as an important regulator. We show that BMP-4 signaling induces a dormant non-cycling quiescent state (d-qNSCs), whereas combined BMP-4/FGF-2 signaling induces a distinct primed quiescent state poised for cell cycle re-entry. Primed quiescent NSCs (p-qNSCs) are defined by high levels of LRIG1 and CD9, as well as an interferon response signature, and can efficiently engraft into the adult subventricular zone (SVZ) niche. Genetic disruption of Lrig1 in vivo within the SVZ NSCs leads an enhanced proliferation. Mechanistically, LRIG1 primes quiescent NSCs for cell cycle re-entry and EGFR responsiveness by enabling EGFR protein levels to increase but limiting signaling activation. LRIG1 is therefore an important functional regulator of NSC exit from quiescence.

scholarly journals Functional maturation of human neural stem cells in a 3D bioengineered brain model enriched with fetal brain-derived matrix

2019 ◽  
Author(s):  
Disha Sood ◽  
Dana M. Cairns ◽  
Jayanth M. Dabbi ◽  
Charu Ramakrishnan ◽  
Karl Deisseroth ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Brain Tissue ◽  
Fetal Brain ◽  
Functional Differentiation ◽  
Adult Brain ◽  
Human Neural Stem Cells ◽  
Functional Maturation ◽  
Enriched Cultures

AbstractBrain extracellular matrix (ECM) is often overlooked in vitro brain tissue models, despite its instructive roles during development. Using developmental stage-sourced brain ECM in reproducible 3D bioengineered culture systems, we demonstrate enhanced functional differentiation of human induced neural stem cells (hiNSCs) into healthy neurons and astrocytes. Particularly, fetal brain tissue-derived ECM supported long-term maintenance of differentiated neurons, demonstrated by morphology, gene expression and secretome profiling. Astrocytes were evident within the second month of differentiation, and reactive astrogliosis was inhibited in brain ECM-enriched cultures when compared to unsupplemented cultures. Functional maturation of the differentiated hiNSCs within fetal ECM-enriched cultures was confirmed by calcium signaling and unsupervised cluster analysis. Additionally, the study identified native biochemical cues in decellularized ECM with notable comparisons between fetal and adult brain-derived ECMs. The development of novel brain-specific biomaterials for generating mature in vitro brain models provides an important path forward for interrogation of neuron-glia interactions.

scholarly journals Neural stem cells-from quiescence to differentiation and potential clinical uses

2021 ◽  
Vol 4 (1) ◽  
pp. 23-41
Author(s):  
Alexandra-Elena Dobranici ◽  
Sorina Dinescu ◽  
Marieta Costache
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Molecular Mechanisms ◽  
Adult Brain ◽  
Quiescent State ◽  
Multipotent Stem Cells ◽  
Pathological Conditions ◽  
Mature Neurons ◽  
Direct Cell ◽  
The Brain

Specialised cells of the brain are generated from a population of multipotent stem cells found in the forming embryo and adult brain after birth, called neural stem cells. They reside in specific niches, usually in a quiescent, non-proliferating state that maintains their reservoir. Neural stem cells are kept inactive by various cues such as direct cell-cell contacts with neighbouring cells or by soluble molecules that trigger intracellular responses. They are activated in response to injuries, physical exercise, or hypoxia condition, through stimulation of signaling pathways that are usually correlated with increased proliferation and survival. Moreover, mature neurons play essential role in regulating the balance between active and quiescent state by realising inhibitory or activating neurotransmitters. Understanding molecular mechanisms underlying neuronal differentiation is of great importance in elucidating pathological conditions of the brain and treating neurodegenerative disorders that until now have no efficient therapies.

scholarly journals Adult-Brain-Derived Neural Stem Cells Grafting into a Vein Bridge Increases Postlesional Recovery and Regeneration in a Peripheral Nerve of Adult Pig

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Olivier Liard ◽  
Stéphanie Segura ◽  
Emmanuel Sagui ◽  
André Nau ◽  
Aurélie Pascual ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Fluorescent Protein ◽  
Longitudinal Axis ◽  
Adult Brain ◽  
Venous Graft ◽  
Neuronal Phenotype ◽  
Leg Extension ◽  
Repair Strategy

We attempted transplantation of adult neural stem cells (ANSCs) inside an autologous venous graft following surgical transsection ofnervis cruraliswith 30 mm long gap in adult pig. The transplanted cell suspension was a primary culture of neurospheres from adult pig subventricular zone (SVZ) which had been labeledin vitrowith BrdU or lentivirally transferred fluorescent protein. Lesion-induced loss of leg extension on the thigh became definitive in controls but was reversed by 45–90 days after neurosphere-filled vein grafting. Electromyography showed stimulodetection recovery in neurosphere-transplanted pigs but not in controls. Postmortem immunohistochemistry revealed neurosphere-derived cells that survived inside the venous graft from 10 to 240 post-lesion days and all displayed a neuronal phenotype. Newly formed neurons were distributed inside the venous graft along the severed nerve longitudinal axis. Moreover, ANSC transplantation increased CNPase expression, indicating activation of intrinsic Schwann cells. Thus ANSC transplantation inside an autologous venous graft provides an efficient repair strategy.

scholarly journals Functional maturation of human neural stem cells in a 3D bioengineered brain model enriched with fetal brain-derived matrix

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Disha Sood ◽  
Dana M. Cairns ◽  
Jayanth M. Dabbi ◽  
Charu Ramakrishnan ◽  
Karl Deisseroth ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Brain Tissue ◽  
Fetal Brain ◽  
Functional Differentiation ◽  
Adult Brain ◽  
Human Neural Stem Cells ◽  
Functional Maturation ◽  
Enriched Cultures

AbstractBrain extracellular matrix (ECM) is often overlooked in vitro brain tissue models, despite its instructive roles during development. Using developmental stage-sourced brain ECM in reproducible 3D bioengineered culture systems, we demonstrate enhanced functional differentiation of human induced neural stem cells (hiNSCs) into healthy neurons and astrocytes. Particularly, fetal brain tissue-derived ECM supported long-term maintenance of differentiated neurons, demonstrated by morphology, gene expression and secretome profiling. Astrocytes were evident within the second month of differentiation, and reactive astrogliosis was inhibited in brain ECM-enriched cultures when compared to unsupplemented cultures. Functional maturation of the differentiated hiNSCs within fetal ECM-enriched cultures was confirmed by calcium signaling and spectral/cluster analysis. Additionally, the study identified native biochemical cues in decellularized ECM with notable comparisons between fetal and adult brain-derived ECMs. The development of novel brain-specific biomaterials for generating mature in vitro brain models provides an important path forward for interrogation of neuron-glia interactions.

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