Neural stem cell spacing questions their self-renewal

Mineyeva, Olga A.; Koulakov, Alexei A.; Enikolopov, Grigori

doi:10.18632/aging.101519

Cited by 4 publications

(3 citation statements)

References 7 publications

(7 reference statements)

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“…Therefore, we next asked whether the rate of symmetric division of stem cells was modified by irradiation. We reasoned that symmetric divisions of RGLs would alter the spatial distribution of BrdU-labeled RGLs since such cells would generate pairs of closely positioned cells within the sectioned DG volume (Mineyeva O. et al, 2018; Mineyeva O.A. et al, 2018).…”

Section: Resultsmentioning

confidence: 99%

Radiation Induces Distinct Changes in Defined Subpopulations of Neural Stem and Progenitor Cells in the Adult Hippocampus

et al. 2019

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While irradiation can effectively treat brain tumors, this therapy also causes cognitive impairments, some of which may stem from the disruption of hippocampal neurogenesis. To study how radiation affects neurogenesis, we combine phenotyping of subpopulations of hippocampal neural stem and progenitor cells with double- and triple S-phase labeling paradigms. Using this approach, we reveal new features of division, survival, and differentiation of neural stem and progenitor cells after exposure to gamma radiation. We show that dividing neural stem cells, while susceptible to damage induced by gamma rays, are less vulnerable than their rapidly amplifying progeny. We also show that dividing stem and progenitor cells that survive irradiation are suppressed in their ability to replicate 0.5–1 day after the radiation exposure. Suppression of division is also observed for cells that entered the cell cycle after irradiation or were not in the S phase at the time of exposure. Determining the longer term effects of irradiation, we found that 2 months after exposure, radiation-induced suppression of division is partially relieved for both stem and progenitor cells, without evidence for compensatory symmetric divisions as a means to restore the normal level of neurogenesis. By that time, most mature young neurons, born 2–4 weeks after the irradiation, still bear the consequences of radiation exposure, unlike younger neurons undergoing early stages of differentiation without overt signs of deficient maturation. Later, 6 months after an exposure to 5 Gy, cell proliferation and neurogenesis are further impaired, though neural stem cells are still available in the niche, and their pool is preserved. Our results indicate that various subpopulations of stem and progenitor cells in the adult hippocampus have different susceptibility to gamma radiation, and that neurogenesis, even after a temporary restoration, is impaired in the long term after exposure to gamma rays. Our study provides a framework for investigating critical issues of neural stem cell maintenance, aging, interaction with their microenvironment, and post-irradiation therapy.

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Section: Resultsmentioning

confidence: 99%

Radiation Induces Distinct Changes in Defined Subpopulations of Neural Stem and Progenitor Cells in the Adult Hippocampus

et al. 2019

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“…Also, unlike typical asymmetric division (q2a, Fig. 1 A ), which creates NPC and maintains NSC pool (Kaslin et al, 2009; Mineyeva et al, 2018), a direct division or conversion into PMCs can cause NSC depletion (Barbosa et al, 2015). The latter, however, is unlikely in HCI fish because no increase in PMC numbers is observed.…”

Section: Discussionmentioning

confidence: 99%

Cell Kinetics in the Adult Neurogenic Niche and Impact of Diet-Induced Accelerated Aging

et al. 2019

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Neurogenesis in the adult brain, a powerful mechanism for neuronal plasticity and brain repair, is altered by aging and pathological conditions, including metabolic disorders. The search for mechanisms and therapeutic solutions to alter neurogenesis requires understanding of cell kinetics within neurogenic niches using a high-throughput quantitative approach. The challenge is in the dynamic nature of the process and multiple cell types involved, each having several potential modes of division or cell fate. Here we show that cell kinetics can be revealed through a combination of the BrdU/EdU pulse-chase, based on the circadian pattern of DNA replication, and a differential equations model that describes time-dependent cell densities. The model is validated through the analysis of cell kinetics in the cerebellar neurogenic niche of normal young adult male zebrafish, with cells quantified in 2D (sections), and with neuronal fate and reactivation of stem cells confirmed in 3D whole-brain images (CLARITY). We then reveal complex alterations in cell kinetics associated with accelerated aging due to chronic high caloric intake. Low activity of neuronal stem cells in this condition persists 2 months after reverting to normal diet, and is accompanied by overproduction of transient amplifying cells, their accelerated cell death, and slow migration of postmitotic progeny. This combined experimental and mathematical approach should allow for relatively high-throughput analysis of early signs of pathological and age-related changes in neurogenesis, evaluation of specific therapeutic targets, and drug efficacy. SIGNIFICANCE STATEMENT Understanding normal cell kinetics of adult neurogenesis and the type of cells affected by a pathological process is needed to develop effective prophylactic and therapeutic measures directed at specific cell targets. Complex time-dependent mechanisms involved in the kinetics of multiple cell types require a combination of experimental and mathematical modeling approaches. This study demonstrates such a combined approach by comparing normal neurogenesis with that altered by diet-induced accelerated aging in adult zebrafish.

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“…Here, there is substantial evidence regarding the cell cycle and lineage tracing of SVZ-derived NPCs, as well as factors that play an important role in regulating SVZ-derived NPC proliferation in the adult rodent brain (78,80,(82)(83)(84). Research suggests that the majority of rodent hippocampal NPCs divide asymmetrically and that there may be a limited number of proliferative cycles emerging from the rodent SGZ (85)(86)(87)(88). In contrast, recent research has demonstrated that the majority of SVZ-derived NPCs divide symmetrically and that ∼20% of these B1 cells symmetrically self-renew, allowing neurogenesis to continue throughout adulthood (82).…”

Section: Endogenous Stem Cell Sources In the Postnatal Brainmentioning

confidence: 99%

Tissue Engineering and Biomaterial Strategies to Elicit Endogenous Neuronal Replacement in the Brain

et al. 2020

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Neurogenesis in the postnatal mammalian brain is known to occur in the dentate gyrus of the hippocampus and the subventricular zone. These neurogenic niches serve as endogenous sources of neural precursor cells that could potentially replace neurons that have been lost or damaged throughout the brain. As an example, manipulation of the subventricular zone to augment neurogenesis has become a popular strategy for attempting to replace neurons that have been lost due to acute brain injury or neurodegenerative disease. In this review article, we describe current experimental strategies to enhance the regenerative potential of endogenous neural precursor cell sources by enhancing cell proliferation in neurogenic regions and/or redirecting migration, including pharmacological, biomaterial, and tissue engineering strategies. In particular, we discuss a novel replacement strategy based on exogenously biofabricated "living scaffolds" that could enhance and redirect endogenous neuroblast migration from the subventricular zone to specified regions throughout the brain. This approach utilizes the first implantable, biomimetic tissue-engineered rostral migratory stream, thereby leveraging the brain's natural mechanism for sustained neuronal replacement by replicating the structure and function of the native rostral migratory stream. Across all these strategies, we discuss several challenges that need to be overcome to successfully harness endogenous neural precursor cells to promote nervous system repair and functional restoration. With further development, the diverse and innovative tissue engineering and biomaterial strategies explored in this review have the potential to facilitate functional neuronal replacement to mitigate neurological and psychiatric symptoms caused by injury, developmental disorders, or neurodegenerative disease.

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Neural stem cell spacing questions their self-renewal

Cited by 4 publications

References 7 publications

Radiation Induces Distinct Changes in Defined Subpopulations of Neural Stem and Progenitor Cells in the Adult Hippocampus

Radiation Induces Distinct Changes in Defined Subpopulations of Neural Stem and Progenitor Cells in the Adult Hippocampus

Cell Kinetics in the Adult Neurogenic Niche and Impact of Diet-Induced Accelerated Aging

Tissue Engineering and Biomaterial Strategies to Elicit Endogenous Neuronal Replacement in the Brain

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