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Cited by 163Neurogenesis and neuroplasticity mechanismsNeuroinflammation and Neurodegeneration MechanismsNeuroscience and Neuropharmacology Research

Defining the Adult Neural Stem Cell Niche Proteome Identifies Key Regulators of Adult Neurogenesis

Open access
Kjell, Jacob, Fischer-Sternjak, Judith, Thompson, Amelia J., Friess, Christian, Sticco, Matthew J., Salinas, Favio, Cox, Jürgen, Martinelli, David C. +4 more·2020·Cell Stem Cell
DOI 10.1016/j.stem.2020.01.002PMC PMC7005820
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Abstract

The mammalian brain contains few niches for neural stem cells (NSCs) capable of generating new neurons, whereas other regions are primarily gliogenic. Here we leverage the spatial separation of the sub-ependymal zone NSC niche and the olfactory bulb, the region to which newly generated neurons from the sub-ependymal zone migrate and integrate, and present a comprehensive proteomic characterization of these regions in comparison to the cerebral cortex, which is not conducive to neurogenesis and integration of new neurons. We find differing compositions of regulatory extracellular matrix (ECM) components in the neurogenic niche. We further show that quiescent NSCs are the main source of their local ECM, including the multi-functional enzyme transglutaminase 2, which we show is crucial for neurogenesis. Atomic force microscopy corroborated indications from the proteomic analyses that neurogenic niches are significantly stiffer than non-neurogenic parenchyma. Together these findings provide a powerful resource for unraveling unique compositions of neurogenic niches.

AI snapshot

Written from the paper’s full text.

TL;DR

This paper provides a comprehensive proteomic and biochemical characterization of the adult mouse sub-ependymal zone (SEZ) neural stem cell niche, olfactory bulb (OB), and non-neurogenic cortex, identifying niche-specific extracellular matrix proteins and stiffness. It functionally validates transglutaminase 2 (Tgm2) as a regulator of adult neurogenesis and shows neurogenic niches are stiffer than non-neurogenic parenchyma.

Key findings

  • Deep proteomics identified 10,923 proteins in library samples and 6,690 in library-matched single-shot samples across cortex, OB, SEZ, and medial sub-ependymal zone (MEZ); 4,786 proteins had differential abundance among the four regions (ANOVA, FDR = 0.05). Quantitative detergent solubility profiling identified 8,308 proteins, with 1,208 showing significantly different solubility profiles among cortex, OB, and SEZ (two-way ANOVA, p ≤ 0.05).
  • Neurogenic niches showed distinct matrisome composition: core matrisome proteins were most abundant in cortex, while SEZ/MEZ shared annexin and S100 proteins, and OB/SEZ were rich in serpins, vitronectin, and Tenascin-C. S100a6 and C1ql3 were enriched in the SEZ and marked NSCs rather than neuroblasts; quiescent NSCs were identified as the main source of local ECM components.
  • Tgm2 was enriched in SEZ and MEZ, produced by ependymal cells and NSCs, and functionally promoted neurogenesis: Z-DON reduced retrovirally labeled clones and neuronal clones in vitro, Tgm2 siRNA reduced neuronal clones, and 4-day intraventricular Z-DON reduced EdU+/Dcx− TAPs in vivo (p ≤ 0.05), with a trend at 7 days (p = 0.0537).
  • Atomic force microscopy showed SEZ and MEZ were significantly stiffer than cortex and striatum, and SEZ was significantly stiffer than MEZ; OB was stiffest among regions. Primary SEZ cells on 200-Pa hydrogels produced more than double the number of Dcx+ neuroblasts compared with 100-Pa hydrogels.

Methods

  • LMSS proteomics: cryo-microdissection of cortex, OB, SEZ, and MEZ from male C57BL/6J mice aged 8–10 weeks; n = 4 single-shot samples per region plus pooled library samples; MaxQuant label-free quantification, PCA, ANOVA with FDR = 0.05, and annotation enrichment.
  • QDSP: sequential detergent extraction of cortex, OB, and SEZ into four protein fractions; n = 4 samples per region after omitting one low-protein sample; 8,308 proteins quantified and solubility profiles compared by two-way ANOVA.
  • Functional validation: primary SEZ cultures with retroviral clonal analysis, Tgm2 inhibitors Z-DON/Boc-DON, and Tgm2 siRNA; intraventricular osmotic pump infusion of Z-DON with EdU labeling; AFM stiffness measurements on coronal slices; primary SEZ culture on 100- and 200-Pa hydrogels; immunohistochemistry, FACS, qPCR, and comparison with scRNA-seq/microarray data.

Limitations

  • The paper does not state a dedicated limitations section.
  • Evident from the text: proteomics, osmotic pump, and AFM experiments used only male mice (8–10 weeks, 10–12 weeks, and 8 weeks, respectively), which may limit generalizability across sex and age.
  • Evident from the text: the in vitro stiffness effect on neuroblast percentage depended on cell density (data not shown), and one QDSP sample was omitted due to low protein content, leaving n = 4 per region; Tgm2’s in vivo extracellular versus intracellular contributions remain unresolved because Boc-DON had no effect in the culture system.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.stem.2020.01.002

Cites

108 of 108 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 15 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Neurogenic niches are significantly stiffer than non-neurogenic parenchyma.

    “Atomic force microscopy corroborated indications from the proteomic analyses that neurogenic niches are significantly stiffer than non-neurogenic parenchyma.”
    Quote in the paperSubstantial claim
  • Findingown data

    The MEZ contains many fewer NSCs and Dcx+ neuroblasts than the SEZ.

    “As it contains many fewer NSCs and Dcx+ neuroblasts (Figure 1C) than the SEZ”
    Quote in the paperSubstantial claim
  • Findingown data

    S100a6 and C1ql3 were distinctly enriched among matrisome-associated proteins of the SEZ.

    “These region-specific comparisons determined, S100a6 and C1ql3 among others, to be distinctly enriched among matrisome-associated proteins of the SEZ”
    Quote in the paperSubstantial claim
  • Findingown data

    In total, 4,786 proteins had a differential abundance among the four regions.

    “In total, 4,786 proteins had a differential abundance among the four regions (ANOVA, FDR = 0.05)”
    Quote in the paperSubstantial claim
  • Findingown data

    The SEZ and the MEZ have a more similar proteome than the other two regions.

    “The principal component analysis (PCA) of the four regions revealed that the SEZ and the MEZ have a more similar proteome than the other two regions”
    Quote in the paperNot a substantial claim
  • May combine two claims. 33
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 16

  • May combine two claims.

    Findingown data

    A total of 10,923 proteins were identified in the library samples and 6,690 in LMSS samples.

    “We identified a total of 10,923 proteins in the library samples (four pooled tissue samples from each region) and 6,690 in LMSS samples (n = 4 per region)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Brain core matrisome proteins were enriched in the fourth fraction and thus more insoluble, whereas matrisome-associated proteins were most abundant in the first fraction and thus more soluble.

    “we found “brain” core matrisome proteins, such as collagens and laminins, to be enriched in the fourth fraction and thus more insoluble, whereas matrisome-associated proteins, such as S100 proteins and serpins, were most abundant in the first fraction and thus more soluble”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    S100a6 staining labeled NSCs, but not neuroblasts.

    “S100a6 staining labeled NSCs (slow dividing nestin+ cells in the SEZ; Figures S3B, S3C, and S3F), but not neuroblasts (Dcx+; Figures 2D, 2G, and S3A–S3C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    C1ql3-mVenus+ cells in the SEZ were Dcx negative, nestin+ and S100a6+ NSCs.

    “In the SEZ, however, C1ql3-mVenus+ cells were Dcx negative, i.e., not neuroblasts but nestin+ and S100a6+ NSCs”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The OB and the SEZ are particularly rich in serpins, vitronectin, and Tnc, whereas the SEZ and the MEZ share high levels of annexin and several S100 proteins.

    “The OB and the SEZ are particularly rich in serpins, vitronectin, and Tnc, whereas the SEZ and the MEZ share high levels of annexin and several S100 proteins”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Of 158 matrisome proteins compared, 78 had a significantly different distribution in the respective regions, with the somatosensory cortex most abundant with extracellular matrix proteins.

    “We compared 158 matrisome proteins and 78 of these had a significantly different distribution in the respective regions, of which the somatosensory cortex was found to be most abundant with extracellular matrix proteins.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The reduced number of neuronal progeny after knockdown of Tgm2 was not due to cell death, as control and knockdown conditions had equal numbers of cells.

    “Notably, the reduced number of neuronal progeny after knockdown of Tgm2 was not due to cell death, as the control and knockdown condition had equal numbers of cells (Figure 6K).”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    Both the SEZ and the MEZ regions were significantly stiffer than the cortex and striatum, and the SEZ was significantly stiffer than the MEZ (p≤0.05, Mann-Whitney, two tailed).

    “Both the SEZ and the MEZ regions were significantly stiffer (Figure 7B), and the SEZ, the main site of neurogenesis, was significantly stiffer than the MEZ, where few neuroblasts arise (Bordiuk et al., 2014) (p ≤ 0.05, Mann-Whitney, two tailed).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Blocking Tgm2 for 4 days in vivo affected mostly the number of TAPs (EdU+/Dcx−), whereas proliferating neuroblasts (EdU+/Dcx+) remained similar to control; this trend was largely maintained after 7 days.

    “After 4 days Z-DON treatment, we found a significant reduction in TAPs (EdU+/Dcx−), whereas proliferating neuroblasts (EdU+/Dcx+) remained similar to control (Data are presented as mean ± SEM. ∗p ≤ 0.05, two-tailed t test). This trend continued after 7 days treatment (Data are presented as mean ± SEM. p = 0.0537, two-tailed t test).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Many of the SEZ-enriched proteins are upregulated at early postnatal stages when the adult NSC niche forms.

    “Indeed, many of the SEZ-enriched proteins are upregulated at early postnatal stages when the adult NSC niche forms (F.V., P.S., and M. Götz, unpublished data).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    C1ql3 is enriched with a specific solubility profile in the SEZ-niche, and NSCs are the major source.

    “Here we found it enriched with a specific solubility profile in the SEZ-niche and identified NSCs as the major source.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    S100a6 and C1ql3 are soluble ECM-associated proteins enriched in NSCs of the SEZ.

    “S100a6 and C1ql3 were both soluble ECM-associated proteins that we found enriched in NSCs of the SEZ.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Tgm2 is the only Tgm family member detectable in the SEZ (Tgm1, Tgm3, Tgm5, and Tgm6 were not detectable).

    “Notably, Tgm2 is the only family member detectable in the SEZ (Tgm1, Tgm3, Tgm5, and Tgm6 were not detectable).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There is no evidence for a general increase in blood proteins from allegedly leaky vessels in the SEZ tissue; rather, genes for soluble ECM proteins (e.g., serpinb6, annexin 1, and annexin 5) are expressed by cells in the SEZ, mostly qNSCs.

    “However, we found no evidence for a general increase in blood proteins from allegedly leaky vessels (Tavazoie et al., 2008) in the SEZ tissue (Figures S2D and S2E) but rather expression of these genes (e.g., serpinb6, annexin 1, and annexin 5) by cells in the SEZ (Figure 2I), mostly qNSCs (Figure S6A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Tgm2 immunoreactivity is found in ependymal cells and NSCs that extend an apical process to the ventricle, but not in neuroblasts (Dcx+).

    “Tgm2 immunoreactivity was found in ependymal cells (Figures 6A and 6B) and NSCs (hGFAP-GFP+; see Beckervordersandforth et al., 2010, Codega et al., 2014) that extend an apical process to the ventricle (Figure 6B), but not in neuroblasts (Dcx+) (Figure 6C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the OB, stiffness increases from the RMS toward the granule cell layer (GCL), which was stiffer throughout the OB parenchyma.

    “Assessing the OB, we also found an increase in stiffness from the RMS toward the granule cell layer (GCL), which was stiffer throughout the OB parenchyma (Figures 7C and 7D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    C1ql3 is enriched in the SEZ only at the protein level and was not identified as a NSC marker in RNA analysis.

    “Notably, C1ql3 is enriched in the SEZ only at the protein level and was hence not identified as a NSC marker in RNA analysis (Figure S6B).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Findingnone given

    The outcome of the stiffness difference appears to depend on cell density.

    “even though the outcome of this difference appears to depend on cell density (data not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Cells isolated by FACS that contain the highest Tgm2 protein levels (ependymal cells and NSCs) also had high Tgm2 mRNA levels, whereas TAPs and neuroblasts contained very low mRNA levels.

    “Consistent with ependymal cells and NSCs containing the highest protein levels, these cells isolated by fluorescence-activated cell sorting (Beckervordersandforth et al., 2010, Fischer et al., 2011) also had high Tgm2 mRNA levels, whereas TAPs and neuroblasts contained very low mRNA levels (Figure 6D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Many matrix-associated proteins are more soluble in the neurogenic niches, and several core-matrix proteins (Hapln1, Tnc, and Thbs4) are more soluble in the neurogenic niches compared to other brain regions and tissues.

    “Indeed, many matrix-associated proteins are more soluble in the neurogenic niches, and we even found several core-matrix proteins to be more soluble in the neurogenic niches compared to other brain regions and tissues (Figure S5C). This includes Hapln1, Tnc, and Thbs4.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In the adult mammalian brain, NSC niches are unique in supporting neurogenesis, as only gliogenesis takes place in the remainder of the brain.

    “In the adult mammalian brain, the neural stem cell (NSC) niches are unique in supporting neurogenesis (Conover and Todd, 2017, Ruddy and Morshead, 2018), as only gliogenesis takes place in the remainder of the brain”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Conover and Todd, 2017

      Not checked in the free run.

    • cites Ruddy and Morshead, 2018

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The SEZ generates neuroblasts that migrate to the OB, where they differentiate and integrate.

    “The largest NSC niche, the sub-ependymal zone (SEZ), generates neuroblasts that migrate to the distant olfactory bulb (OB), where they differentiate and integrate”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lim and Alvarez-Buylla, 2016 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    The mature brain parenchyma allows neither neurogenesis nor integration of new neurons in the absence of injury.

    “In contrast to the above-described niches, the mature brain parenchyma allows neither neurogenesis nor integration of new neurons in the absence of injury”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Frisén, 2016 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    For proteomics, osmotic pump, and AFM experiments, only male C57BL/6J mice were used (aged 8-10, 10-12, and 8 weeks respectively) to reduce potential variability.

    “For the proteomics experiments, only male C57BL/6J mice between 8-10 weeks were used, for osmotic pump experiments, only male C57Bl6/J mice between 10-12 weeks were used, and for AFM experiments, only male C57Bl6/J mice aged 8 weeks were used (to reduce any potential variability).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    FACS gates were set by the use of isotype controls.

    “Gates were set by the use of isotype controls (Fischer et al., 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Fischer et al., 2011 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Quality and concentration of total RNA was examined with the Agilent Bioanalyzer.

    “Quality and concentration of total RNA was examined with the Agilent Bioanalyzer.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Hapln1 and Ncan may contribute less to PNNs in the OB compared to the Cx, constituting a composition of PNN proteins that may be involved in allowing constant synaptic plasticity in the OB.

    “which suggests that these proteins may contribute less to PNNs in the OB compared to the Cx and hence constitute a composition of PNN proteins that may be involved in allowing constant synaptic plasticity in the OB.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The neuron-associated ECM has a different composition and architecture compared to the insoluble BM proteins, and has very little contribution to tissue stiffness.

    “Our solubility profiles show that the neuron-associated ECM clearly has a different composition and architecture compared to the insoluble BM proteins, and our data suggest it has very little contribution to tissue stiffness.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The additional presence of Tgm2 in NSCs implies possible autocrine or cell-intrinsic effects.

    “but its additional presence in NSCs implies possible autocrine or cell-intrinsic effects that we explored next.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Components of the proteome contribute to regulate the niche-specific mechanical properties, which affects neurogenesis.

    “suggesting that components of the proteome contribute to regulate these niche-specific mechanical properties, which affects neurogenesis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The SEZ contains more or larger BM structures, as suggested by more insoluble ECM components (Lamb2, Nid1, Hspg2) in the SEZ compared to the MEZ.

    “Conversely, we found more insoluble ECM components that may relate to the increased stiffness of the SEZ, such as Laminin-b2 (Lamb2), Nidogen-1 (Nid1), and Perlecan (Hspg2) in the SEZ compared to the MEZ (Figure S2B), which suggests that the SEZ contains more or larger BM structures.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Tgm2 may promote proliferation or survival.

    “suggesting a possible role of Tgm2 in promoting proliferation or survival.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    qPCR expression levels were normalized to GAPDH.

    “qPCR was performed on an Opticon (BIO-RAD) with iQ SYBR Green Supermix (BIO-RAD) and expression levels were normalized to GAPDH.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The desired gel-stiffness was confirmed with Atomic force microscopy (AFM).

    “The desired gel-stiffness was confirmed with Atomic force microscopy (AFM).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The in vivo phenotype is consistent with reduced clone numbers and effects on pure neuronal clones in vitro, as TAPs almost exclusively generate neuroblasts.

    “This phenotype obtained in vivo is consistent with reduced clone numbers (Figure 6G) and effects on pure neuronal clones (Figures 6H and 6J) in vitro, as TAPs almost exclusively generate neuroblasts.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: TAPs almost exclusively generate neuroblasts.

  • May combine two claims.

    Interpretationown data

    The structural ECM is not enriched in the neurogenic niche, including the typical 'soft' structural brain ECM, although individual proteins with these properties can be found enriched in both the SEZ and the OB.

    “The structural ECM is thus not enriched in the neurogenic niche, including the typical “soft” structural brain ECM, although individual proteins with these properties can be found enriched in both the SEZ and the OB.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The lamins may have a different composition or associate to cytoskeletal proteins through proteins such as Nesprin-2 (Syne2), which had similar distinct solubility characteristics in the OB.

    “which suggests they may have a different composition or associate to cytoskeletal proteins through proteins such as Nesprin-2 (Syne2), which had similar distinct solubility characteristics in the OB.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    For both protein and peptide level, FDR was set to 0.01.

    “For both protein and peptide level we set FDR to 0.01 and only peptides with an amino-acid length of seven or more were considered.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    AFM cantilever spring constants were determined using the thermal noise method.

    “For stiffness measurements, the spring constant k of tipless silicon cantilevers (Arrow-TL1, NanoWorld) were determined using the thermal noise method (Hutter and Bechhoefer, 1993) and cantilevers with k of 0.01-0.04 N/m (for olfactory bulb (OB) measurements) or 0.05-0.07 N/m (for SEZ/MEZ measurements) were selected.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hutter and Bechhoefer, 1993

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    LFQ intensities are normalized median mass spectra intensity values that allow quantification to be performed with any peptide and protein fractionation while maintaining high accuracy.

    “LFQ intensities are normalized median mass spectra intensity values that allow this quantification to be performed with any peptide and protein fractionation while maintaining high accuracy (Cox et al., 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Cox et al., 2014 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Label-free protein quantification was restricted to proteins identified with at least two unique peptides.

    “The label-free protein quantification was restricted to proteins identified with at least two unique peptides.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Only peptides with an amino-acid length of seven or more were considered.

    “For both protein and peptide level we set FDR to 0.01 and only peptides with an amino-acid length of seven or more were considered.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Study design and conductnone given

    The use of spherical probes ensured a consistent contact area with the sample surface and prevented damage to the slices.

    “The use of spherical probes ensured a consistent contact area with the sample surface and prevented damage to the slices.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    One QDSP sample was omitted from further bioinformatics analysis because two of its brain regions had a protein fraction with very low protein content and several fractions with lower protein identification, resulting in 4 samples per region.

    “Among the QDSP samples, there was one sample with two of the brain regions that had protein fraction with very low protein content and several fractions with lower protein identification. Thus, we omitted the whole sample from further bioinformatics analysis. This resulted in 4 samples per region (each with their respective four solubility fractions).”
    Quote in the paperNot a substantial claim
44 of 44

  • The paper relies on this without support.

    No comprehensive proteomic analysis of the NSC niche has yet been performed.

    “However, no comprehensive proteomic analysis of this important niche has yet been performed.”

  • The paper relies on this without support.

    The actual composition of the NSC niche ECM is largely unknown, as are potential differences in ECM composition between the OB and brain parenchyma.

    “its ECM composition is expected to differ from the brain parenchyma, but the actual composition is largely unknown, as are potential differences in ECM composition between the OB and brain parenchyma.”

  • The paper relies on this without support.

    Detergent de-cellularization has not yet been done in the NSC niches.

    “but this has not yet been done in the NSC niches.”

  • The paper relies on this without support.

    The mechanical properties of the adult stem cell niche are currently unknown.

    “However, the mechanical properties of the adult stem cell niche are currently unknown.”

  • The paper relies on this without support.

    The NSC niche contains no neurons, and hence no PNNs.

    “As the NSC niche contains no neurons, and hence no PNNs”

  • The paper relies on this without support.

    TAPs almost exclusively generate neuroblasts.

    “as TAPs almost exclusively generate neuroblasts.”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Extraction description gives conflicting numbers of detergent mixtures

    Minor

    The Results describe extraction with four distinct detergent mixtures. The methods instead describe three extraction buffers, with the fourth fraction consisting of residual insoluble material.

  • Figure 4D reverses the significance threshold

    Minor

    The caption labels proteins significant at FDR ≥ 0.05, whereas the analysis methods specify a significance cutoff of ≤ 0.05 for differences between regional solubility profiles.

  • Figure 4H reverses the significance threshold

    Minor

    The Figure 4H caption calls solubility differences significant at p ≥ 0.05, but the methods specify p ≤ 0.05 for the matrisome proteins shown in that figure.

  • Different counts for proteins with altered solubility

    Minor

    The Figure 4D caption reports 1,216 proteins with significantly different solubility, while the Results report 1,208 for the same comparison.

4 of 4

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Authors
Kjell, J., Fischer-Sternjak, J., Thompson, A. J., Friess, C., Sticco, M. J., Salinas, F., Cox, J., Martinelli, D. C., Ninkovic, J., Franze, K., Schiller, H. B., & Götz, M.
Affiliations
  • Helmholtz Munich (DE)
  • University of Cambridge (GB)
  • Ludwig-Maximilians-Universität München (DE)
  • UConn Health (US)
  • Max Planck Institute of Biochemistry (DE)
Corresponding author
Götz, Magdalena
ORCID
Venue
Cell Stem Cell
Publisher
Elsevier BV
Published
2020-02
Volume
26
Issue
2
Pages
277-293.e8
ISSN
  • 1875-9777 (ISSN-L)
  • 1934-5909
DOI
10.1016/j.stem.2020.01.002
PMC
PMC7005820
OpenAlex
W3005091816
Cited by
163
References
109
Citations by year
2026: 12 · 2025: 25 · 2024: 24 · 2023: 28 · 2022: 28 · 2021: 29 · 2020: 17
FWCI
10.53
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell stem cell (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion, cc-by-nc-nd)
  • Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by-nc-nd)
  • Site cant be reached (submittedVersion, cc-by-nc-nd)
  • MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
Funders
  • European Research Council (340793, 772426)
  • Svenska Sällskapet för Medicinsk Forskning
  • Deutsche Forschungsgemeinschaft (SFB870, SPP1738, SPP1751)
  • European Commission (S-700982-5008-001)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
adult neurogenesis, neural stem cell niche, olfactory bulb, extracellular matrix, tissue transglutaminase, tissue stiffness, quiescent neural stem cells, cerebral cortex, gliogenesis, neural integration
MeSH terms
Animals, Proteome, Proteomics, Stem Cell Niche, Neurogenesis, Neural Stem Cells

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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