Distinct Neural Stem Cell Populations Give Rise to Disparate Brain Tumors in Response to N-MYC

AbstractStem cell populations within developing embryos are diverse, composed of many different sub-populations of cells with varying developmental potential. The structure of stem cell populations in cell culture remains poorly understood and presents a barrier to differentiating stem cells for therapeutic applications. In this paper we develop a framework for controlling the architecture of stem cell populations in cell culture using high-throughput single cell mRNA-seq and computational analysis. We find that the transcriptional diversity of neural stem cell populations collapses in cell culture. Cell populations are depleted of committed neuron progenitor cells and become dominated by a single pre-astrocytic cell population. By analyzing the response of neural stem cell populations to forty distinct signaling conditions, we demonstrate that signaling environments can restructure cell populations by modulating the relative abundance of pre-astrocyte and pre-neuron subpopulations according to a simple linear code. One specific combination of BMP4, EGF, and FGF2 ligands switches the default population balance such that 70% of cells correspond to the committed neurons. Our work demonstrates that single-cell RNA-seq can be applied to modulate the diversity of in vitro stem cell populations providing a new strategy for population-level stem cell control.HighlightsNatural progenitor diversity in the brain collapses during in vitro culture to a single progenitor typeLoss of progenitor diversity alters fate potential of cells during differentiationLarge scale single-cell signaling screen identifies signals that reshape population structure towards neuronal cell typesSignals regulate population structure according to a simple log-linear model

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Faculty Opinions recommendation of Apoptosis differently affects lineage tracing of Lgr5 and Bmi1 intestinal stem cell populations.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717979881.793475656 ◽

2013 ◽

Author(s):

Malcolm Alison

Keyword(s):

Stem Cell ◽

Lineage Tracing ◽

Intestinal Stem Cell ◽

Cell Populations ◽

Stem Cell Populations

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Chromatin and transcription factor profiling in rare stem cell populations using CUT&Tag

STAR Protocols ◽

10.1016/j.xpro.2021.100751 ◽

2021 ◽

Vol 2 (3) ◽

pp. 100751

Author(s):

Yuefeng Li ◽

Kiran Nakka ◽

Thomas Olender ◽

Philippe Gingras-Gelinas ◽

Matthew Man-Kin Wong ◽

...

Keyword(s):

Transcription Factor ◽

Stem Cell ◽

Cell Populations ◽

Stem Cell Populations

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Simultaneous Isolation of Three Different Stem Cell Populations from Murine Skin

PLoS ONE ◽

10.1371/journal.pone.0140143 ◽

2015 ◽

Vol 10 (10) ◽

pp. e0140143 ◽

Cited By ~ 8

Author(s):

Maria Fernanda Forni ◽

Aline Ramos Maia Lobba ◽

Alexandre Hamilton Pereira Ferreira ◽

Mari Cleide Sogayar

Keyword(s):

Stem Cell ◽

Cell Populations ◽

Stem Cell Populations

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Quiescent, Slow-Cycling Stem Cell Populations in Cancer: A Review of the Evidence and Discussion of Significance

Journal of Oncology ◽

10.1155/2011/396076 ◽

2011 ◽

Vol 2011 ◽

pp. 1-11 ◽

Cited By ~ 159

Author(s):

Nathan Moore ◽

Stephen Lyle

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Adult Stem Cells ◽

Cell Populations ◽

Proliferative Potential ◽

Cell Cycle Regulators ◽

Slow Cycling ◽

Stem Cell Populations

Long-lived cancer stem cells (CSCs) with indefinite proliferative potential have been identified in multiple epithelial cancer types. These cells are likely derived from transformed adult stem cells and are thought to share many characteristics with their parental population, including a quiescent slow-cycling phenotype. Various label-retaining techniques have been used to identify normal slow cycling adult stem cell populations and offer a unique methodology to functionally identify and isolate cancer stem cells. The quiescent nature of CSCs represents an inherent mechanism that at least partially explains chemotherapy resistance and recurrence in posttherapy cancer patients. Isolating and understanding the cell cycle regulatory mechanisms of quiescent cancer cells will be a key component to creation of future therapies that better target CSCs and totally eradicate tumors. Here we review the evidence for quiescent CSC populations and explore potential cell cycle regulators that may serve as future targets for elimination of these cells.

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Activation of two distinct Sox9-EGFP-expressing intestinal stem cell populations during crypt regeneration after irradiation

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00519.2011 ◽

2012 ◽

Vol 302 (10) ◽

pp. G1111-G1132 ◽

Cited By ~ 97

Author(s):

Laurianne Van Landeghem ◽

M. Agostina Santoro ◽

Adrienne E. Krebs ◽

Amanda T. Mah ◽

Jeffrey J. Dehmer ◽

...

Keyword(s):

Stem Cell ◽

Cell Populations ◽

Intestinal Epithelial ◽

P53 Signaling ◽

Reporter Mice ◽

Radiation Induced ◽

Molecular Phenotypes ◽

Stem Cell Populations ◽

Induced Changes

Recent identification of intestinal epithelial stem cell (ISC) markers and development of ISC reporter mice permit visualization and isolation of regenerating ISCs after radiation to define their functional and molecular phenotypes. Previous studies in uninjured intestine of Sox9-EGFP reporter mice demonstrate that ISCs express low levels of Sox9-EGFP (Sox9-EGFP Low), whereas enteroendocrine cells (EEC) express high levels of Sox9-EGFP (Sox9-EGFP High). We hypothesized that Sox9-EGFP Low ISCs would expand after radiation, exhibit enhanced proliferative capacities, and adopt a distinct gene expression profile associated with rapid proliferation. Sox9-EGFP mice were given 14 Gy abdominal radiation and studied between days 3 and 9 postradiation. Radiation-induced changes in number, growth, and transcriptome of the different Sox9-EGFP cell populations were determined by histology, flow cytometry, in vitro culture assays, and microarray. Microarray confirmed that nonirradiated Sox9-EGFP Low cells are enriched for Lgr5 mRNA and mRNAs enriched in Lgr5-ISCs and identified additional putative ISC markers. Sox9-EGFP High cells were enriched for EEC markers, as well as Bmi1 and Hopx, which are putative markers of quiescent ISCs. Irradiation caused complete crypt loss, followed by expansion and hyperproliferation of Sox9-EGFP Low cells. From nonirradiated intestine, only Sox9-EGFP Low cells exhibited ISC characteristics of forming organoids in culture, whereas during regeneration both Sox9-EGFP Low and High cells formed organoids. Microarray demonstrated that regenerating Sox9-EGFP High cells exhibited transcriptomic changes linked to p53-signaling and ISC-like functions including DNA repair and reduced oxidative metabolism. These findings support a model in which Sox9-EGFP Low cells represent active ISCs, Sox9-EGFP High cells contain radiation-activatable cells with ISC characteristics, and both participate in crypt regeneration.

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