Ablation of proliferating neural stem cells during early life is sufficient to reduce adult hippocampal neurogenesis

AbstractEnvironmental exposures during early life, but not during adolescence or adulthood, lead to persistent reductions in neurogenesis in the adult hippocampal dentate gyrus (DG). The mechanisms by which early life exposures lead to long-term deficits in neurogenesis remain unclear. Here, we investigated whether targeted ablation of dividing neural stem cells during early life is sufficient to produce long-term decreases in DG neurogenesis. Having previously found that the stem cell lineage is resistant to long-term effects of transient ablation of dividing stem cells during adolescence or adulthood (Kirshenbaum et al., 2014), we used a similar pharmacogenetic approach to target dividing neural stem cells for elimination during early life periods sensitive to environmental insults. We then assessed the Nestin stem cell lineage in adulthood. We found that the adult neural stem cell reservoir was depleted following ablation during the first postnatal week, when stem cells were highly proliferative, but not during the third postnatal week, when stem cells were more quiescent. Remarkably, ablating proliferating stem cells during either the first or third postnatal week led to reduced adult neurogenesis out of proportion to the changes in the stem cell pool, indicating a disruption of the stem cell function or niche following stem cell ablation in early life. These results highlight the first three postnatal weeks as a series of sensitive periods during which elimination of dividing stem cells leads to lasting alterations in adult DG neurogenesis and stem cell function. These findings contribute to our understanding of the relationship between DG development and adult neurogenesis, as well as suggest a possible mechanism by which early life experiences may lead to lasting deficits in adult hippocampal neurogenesis.

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Ablation of proliferating neural stem cells during early life is sufficient to reduce adult hippocampal neurogenesis

Hippocampus ◽

10.1002/hipo.22962 ◽

2018 ◽

Vol 28 (8) ◽

pp. 586-601 ◽

Cited By ~ 6

Author(s):

Mary Youssef ◽

Varsha S. Krish ◽

Greer S. Kirshenbaum ◽

Piray Atsak ◽

Tamara J. Lass ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Early Life ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis

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Early life stress decreases the proliferation and numbers of adult hypothalamic neural stem cells

10.1101/831446 ◽

2019 ◽

Author(s):

Pascal Bielefeld ◽

Maralinde R. Abbink ◽

Anna R. Davidson ◽

Paul J. Lucassen ◽

Aniko Korosi ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Neural Stem Cells ◽

Neural Stem Cell ◽

Life Stress ◽

Early Life ◽

Cell Function ◽

Early Life Stress ◽

Adult Brain ◽

Wide Range

AbstractEarly life stress (ELS) is a potent environmental factor that can confer enduring effects on brain structure and function. Exposure to stress during early life has been linked to a wide range of physiopathological consequences later in life. In particular, ELS has been shown to have lasting effects on neurogenesis in the adult brain, suggesting that ELS is a significant regulator of adult neural stem cell function. Here, we investigated the effect of ELS on the numbers and proliferation of neural stem cells in the hypothalamus of adult mice. We show that ELS has long term negative effects on hypothalamic neural stem cell numbers and on their proliferation. Specifically, ELS reduced the total numbers of PCNA+ cells present in hypothalamic areas surrounding the 3rd ventricle; the numbers of PCNA+/Sox2+/Nestin-GFP+ cells present in the medial eminence at the base of the 3rd ventricle; and the number of β-tanycytes around the ventral 3rd ventricle, without affecting the numbers of α-tanycytes in more dorsal areas. These results suggest that a reduction of proliferation and tanycyte numbers contributes to the effects of ELS on the hypothalamus and its consequent physiological alterations.

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Human ovarian cancer stem cells

Reproduction ◽

10.1530/rep-09-0389 ◽

2010 ◽

Vol 140 (1) ◽

pp. 33-41 ◽

Cited By ~ 65

Author(s):

Sharmila A Bapat

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Cell Lineage ◽

Isolation And Identification ◽

Ovarian Cancer Stem Cells ◽

Normal Organ ◽

Stem Cell Lineage ◽

Cell Clones

The isolation and identification of stem-like cells in solid tumors or cancer stem cells (CSCs) have been exciting developments of the last decade, although these rare populations had been earlier identified in leukemia. CSC biology necessitates a detailed delineation of normal stem cell functioning and maintenance of homeostasis within the organ. Ovarian CSC biology has unfortunately not benefited from a pre-established knowledge of stem cell lineage demarcation and functioning in the normal organ. In the absence of such information, some of the classical parameters such as long-term culture-initiating assays to isolate stem cell clones from tumors, screening and evaluation of other epithelial stem cell surface markers, dye efflux, and label retention have been applied toward the putative isolation of CSCs from ovarian tumors. The present review presents an outline of the various approaches developed so far and the various perspectives revealed that are now required to be dealt with toward better disease management.

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The Neural Stem Cell Lineage Reveals Novel Relationships Among Spermatogonial Germ Stem Cells and Other Pluripotent Stem Cells

Stem Cells and Development ◽

10.1089/scd.2013.0245 ◽

2014 ◽

Vol 23 (7) ◽

pp. 767-778 ◽

Cited By ~ 1

Author(s):

Anouk-Martine Teichert ◽

Schreiber Pereira ◽

Brenda Coles ◽

Radha Chaddah ◽

Susan Runciman ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Neural Stem Cell ◽

Pluripotent Stem Cells ◽

Cell Lineage ◽

Stem Cell Lineage

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Ghrelin gene products rescue cultured adult rat hippocampal neural stem cells from high glucose insult

Journal of Molecular Endocrinology ◽

10.1530/jme-16-0096 ◽

2016 ◽

Vol 57 (3) ◽

pp. 171-184 ◽

Cited By ~ 3

Author(s):

Sehee Kim ◽

Chanyang Kim ◽

Seungjoon Park

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

High Glucose ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Gene Products ◽

Growth Hormone Secretagogue ◽

Phosphohistone H3 ◽

Ghrelin Gene ◽

Hippocampal Neural Stem Cells

Adult hippocampal neurogenesis is decreased in type 2 diabetes, and this impairment appears to be important in cognitive dysfunction. Previous studies suggest that ghrelin gene products (acylated ghrelin (AG), unacylated ghrelin (UAG) and obestatin (OB)) promote neurogenesis. Therefore, we hypothesize that ghrelin gene products may reduce the harmful effects of high glucose (HG) on hippocampal neural stem cells (NSCs). The aim of this study was to investigate the role of these peptides on the survival of cultured hippocampal NSCs exposed to HG insult. Treatment of hippocampal NSCs with AG, UAG or OB inhibited HG-induced cell death and apoptosis. Exposure of cells to the growth hormone secretagogue receptor 1a antagonist abolished the protective effects of AG against HG toxicity, whereas those of UAG or OB were preserved. All three peptides attenuated HG-induced decrease in BrdU-labeled and phosphohistone-H3-labeled cells. We also investigated the effects of ghrelin gene products on the regulation of apoptosis at the mitochondrial level. AG, UAG or OB rescued hippocampal NSCs from HG insult by inhibiting intracellular and mitochondrial reactive oxygen species generation and stabilizing mitochondrial transmembrane potential. In addition, cells treated with ghrelin gene products showed an increased Bcl-2 and decreased Bax levels, thereby increasing the Bcl-2/Bax ratio, inhibiting cytochrome c release and preventing caspase-3 activation. Finally, AG-, UAG- or OB-mediated protection was dependent on the activities of adenosine monophosphate-activated protein kinase/uncoupling protein 2 pathway. Our data indicate that ghrelin gene products may act as survival factors that preserve mitochondrial function and inhibit oxidative stress-induced apoptosis.

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The Impact of Cannabinoid Exposure on Glucocorticoid Receptor Signaling in Neural Stem Cells

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.147 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A73-A73

Author(s):

Nikki Gill ◽

Suban Burale ◽

Neerupma Silswal ◽

Donald Benedict DeFranco ◽

Paula Monaghan-Nichols

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Preterm Birth ◽

Neural Stem Cells ◽

Neural Stem Cell ◽

Cannabis Use ◽

Biological Impact ◽

Proliferation And Differentiation ◽

The Impact

Abstract Preterm birth-birth before 37 weeks of pregnancy-can cause many short- and long-term complications in newborns, including respiratory distress syndrome (RDS). RDS results from incomplete lung development and a surfactant deficiency, and it is a major factor of pre-term mortality. Synthetic glucocorticoids (sGCs) such as Betamethasone or Dexamethasone (Beta, Dex) are administered prenatally to women at risk of pre-term birth to prevent preterm complications. While sGCs are known to improve outcome, they also cause alterations in brain development and neural stem cell biology that are associated with long-term neurological defects. One common recreational drug used during pregnancy is cannabis. Some of the active components of cannabis include cannabinoids, which interact with the endocannabinoid receptor pathway in cells. Cannabinoids have been shown to induce proliferation and differentiation of embryonic neural stem cells (NSCs). We hypothesized that maternal cannabis use activates cannabinoid signaling pathways and leads to changes in glucocorticoid signaling in the developing brain. The purpose of this study was to determine whether cannabis use leads to a better or worse neurological outcome for children born pre-term and treated with sGCs for RDS. Neural stem cell neurospheres (NSCs) were isolated from the cerebral cortex of mice and treated with Vehicle (ethanol), Dex, cannabinoid receptor agonist WIN-55,212-2 (Win), or a combination WinDex. The transcriptional profile induced by exposure to Vehicle, Dex, and WinDex RNA were analyzed using microarray analyses examining the complete expressed genome. Gene Chip profiles indicated that both glucocorticoids and cannabinoids induce distinct transcriptional responses in E14.5 NSCs. The genes involved in proliferation-including S100a11, Jun, and Bex2-were repressed by Dex whereas WinDex rescued some of these expression profiles. Some genes encoding microRNA that inhibit our top target coding genes implicated in proliferation showed a greater induction by Dex compared to WinDex. Quantitative Polymerase Chain Reaction (qPCR) was performed to validate our genes of interest, including Adm, which has been shown to induce neural stem cell proliferation and differentiation. The biological impact of Winn on Dex-induced changes in NSC function were examined by in-vitro proliferation and differentiation studies using antibodies to Tuj1 (neurons), GFAP (glia), and CNPase (immature oligodendrocytes). The experiments indicate that Dex increased neuronal and oligodendrocyte differentiation, while WinDex appeared to reverse this phenotype in neurons. These studies suggest that cannabis use during pregnancy may limit the biological impact sGCs for preterm birth and lead to distinct cellular responses.

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Canonical Notch Signaling Is Dispensable for the Maintenance of Adult Hematopoietic Stem Cells.

Blood ◽

10.1182/blood.v106.11.267.267 ◽

2005 ◽

Vol 106 (11) ◽

pp. 267-267 ◽

Cited By ~ 37

Author(s):

Ivan Maillard ◽

Seth E. Pross ◽

Olga Shestova ◽

Hong Sai ◽

Jon C. Aster ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Hematopoietic Stem Cells ◽

Notch Signaling ◽

Transcriptional Activation ◽

Cell Function ◽

Fetal Life ◽

Hematopoietic Stem

Abstract Canonical Notch signaling operates through a highly conserved pathway that regulates the differentiation and homeostasis of hematopoietic cells. Ligand-receptor binding initiates proteolytic release of the Notch intracellular domain (ICN) which migrates to the nucleus, binds the transcription factor CSL/RBPJk and activates target genes through the recruitment of transcriptional coactivators of the Mastermind-like family (MAML). Notch signaling is essential for the emergence of hematopoietic stem cells (HSCs) during fetal life, but its effects on adult HSCs are controversial. In gain-of-function experiments, activation of Notch signaling in adult HSCs increased their self-renewal potential in vitro and in vivo. However, loss-of-function studies have provided conflicting results as to the role of physiological Notch signaling in HSC maintenance and homeostasis. To address this question, we expressed DNMAML1, a GFP-tagged pan-inhibitor of Notch signaling, in mouse HSCs. We have shown previously that DNMAML1 interferes with the formation of the ICN/CSL/MAML transcriptional activation complex and blocks signaling from all four Notch receptors (Notch1-4) (Maillard, Blood 2004). Transfer of DNMAML1-transduced bone marrow (BM) as compared to control GFP-transduced BM into lethally irradiated recipients gave rise to similar long-term stable expression of GFP for at least 6 months after transplant. DNMAML1 and GFP-transduced cells contributed equally to all hematopoietic lineages, except to the T cell and marginal zone B cell lineages, which are Notch-dependent. Expression of DNMAML1 did not affect the size of the BM progenitor compartment (Lin negative, Sca-1 positive, c-Kit high, or LSK cells), or the proportion of LSK cells that were negative for Flt3 and L-Selectin expression (containing long-term HSCs). The stem cell function of DNMAML1-transduced LSK cells was further assessed with in vivo competitive repopulation assays in lethally irradiated recipients. DNMAML1 and GFP-transduced LSK cells competed equally well with wild-type BM, as judged by their contribution to the myeloid lineage up to 4 months post-transplant, through two successive rounds of transplantation. Our data indicate that canonical Notch signaling is dispensable for the maintenance of stem cell function in adult HSCs.

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Early-life midazolam exposure persistently changes chromatin accessibility to impair adult hippocampal neurogenesis and cognition

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2107596118 ◽

2021 ◽

Vol 118 (38) ◽

pp. e2107596118

Author(s):

Hiroyoshi Doi ◽

Taito Matsuda ◽

Atsuhiko Sakai ◽

Shuzo Matsubara ◽

Sumio Hoka ◽

...

Keyword(s):

Early Life ◽

Therapeutic Strategy ◽

Pediatric Anesthesia ◽

Chromatin Accessibility ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Voluntary Exercise ◽

Early Life Exposure ◽

Mouse Hippocampus

Linkage between early-life exposure to anesthesia and subsequent learning disabilities is of great concern to children and their families. Here we show that early-life exposure to midazolam (MDZ), a widely used drug in pediatric anesthesia, persistently alters chromatin accessibility and the expression of quiescence-associated genes in neural stem cells (NSCs) in the mouse hippocampus. The alterations led to a sustained restriction of NSC proliferation toward adulthood, resulting in a reduction of neurogenesis that was associated with the impairment of hippocampal-dependent memory functions. Moreover, we found that voluntary exercise restored hippocampal neurogenesis, normalized the MDZ-perturbed transcriptome, and ameliorated cognitive ability in MDZ-exposed mice. Our findings thus explain how pediatric anesthesia provokes long-term adverse effects on brain function and provide a possible therapeutic strategy for countering them.

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Secretome Analysis of Mesenchymal Stem Cell Factors Fostering Oligodendroglial Differentiation of Neural Stem Cells In Vivo

International Journal of Molecular Sciences ◽

10.3390/ijms21124350 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4350

Author(s):

Iria Samper Agrelo ◽

Jessica Schira-Heinen ◽

Felix Beyer ◽

Janos Groh ◽

Christine Bütermann ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Mesenchymal Stem Cell ◽

Neural Stem Cells ◽

Cell Lineage ◽

Underlying Mechanism ◽

Tissue Inhibitor Of Metalloproteinase ◽

Specific Cell ◽

Secretome Analysis

Mesenchymal stem cell (MSC)-secreted factors have been shown to significantly promote oligodendrogenesis from cultured primary adult neural stem cells (aNSCs) and oligodendroglial precursor cells (OPCs). Revealing underlying mechanisms of how aNSCs can be fostered to differentiate into a specific cell lineage could provide important insights for the establishment of novel neuroregenerative treatment approaches aiming at myelin repair. However, the nature of MSC-derived differentiation and maturation factors acting on the oligodendroglial lineage has not been identified thus far. In addition to missing information on active ingredients, the degree to which MSC-dependent lineage instruction is functional in vivo also remains to be established. We here demonstrate that MSC-derived factors can indeed stimulate oligodendrogenesis and myelin sheath generation of aNSCs transplanted into different rodent central nervous system (CNS) regions, and furthermore, we provide insights into the underlying mechanism on the basis of a comparative mass spectrometry secretome analysis. We identified a number of secreted proteins known to act on oligodendroglia lineage differentiation. Among them, the tissue inhibitor of metalloproteinase type 1 (TIMP-1) was revealed to be an active component of the MSC-conditioned medium, thus validating our chosen secretome approach.

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