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Fibrinogen induces neural stem cell differentiation into astrocytes in the subventricular zone via BMP signaling

Pous, Lauriane, Deshpande, Sachin S., Nath, Suvra, Mezey, Szilvia, Malik, Subash C., Schildge, Sebastian, Bohrer, Christian, Topp, Könül, Pfeifer, Dietmar, Fernández-Klett, Francisco, Doostkam, Soroush, Galanakis, Dennis K., Taylor, Verdon, Akassoglou, Katerina, Schachtrup, Christian·2020·Nature Communications
DOI 10.1038/s41467-020-14466-yPMC PMC6994610
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Abstract

Neural stem/progenitor cells (NSPCs) originating from the subventricular zone (SVZ) contribute to brain repair during CNS disease. The microenvironment within the SVZ stem cell niche controls NSPC fate. However, extracellular factors within the niche that trigger astrogliogenesis over neurogenesis during CNS disease are unclear. Here, we show that blood-derived fibrinogen is enriched in the SVZ niche following distant cortical brain injury in mice. Fibrinogen inhibited neuronal differentiation in SVZ and hippocampal NSPCs while promoting astrogenesis via activation of the BMP receptor signaling pathway. Genetic and pharmacologic depletion of fibrinogen reduced astrocyte formation within the SVZ after cortical injury, reducing the contribution of SVZ-derived reactive astrocytes to lesion scar formation. We propose that fibrinogen is a regulator of NSPC-derived astrogenesis from the SVZ niche via BMP receptor signaling pathway following injury.

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Figures

Fig. 1 Fibrinogen deposition in the SVZ after cortical injury. a GFAP immunostaining (green) around the lesion core (indicated by yellow dotted line) and in the SVZ. White box indicating enlargement of SVZ showing GFAP expression in the adult SVZ 7 days after PT (right) (n = 4 mice). Scale bars, 369 μm, left and 57 µm, enlargement. b Fibrinogen immunostaining (red) in the lesion core and in the SVZ 1 day after PT. White box indicating enlargement of SVZ showing fibrinogen deposition in the SVZ 1 day after PT (right) (n = 4 mice). Scale bars, 428 μm, left and 120 µm, enlargement. c GFAP (green) and fibrinogen (red) immunostainings in the lesion core (left) and in the SVZ (right) 3, 5 and 7 days after stroke (MCAO). White box indicating enlargement of SVZ showing increased GFAP expression colocalizing with fibrinogen (red) deposition in the SVZ 3 days after stroke. Scale bars, 543 μm, left and 50 µm, right (n = 3 mice). d δ-GFAP (green) and fibrinogen (red) immunostainings in the SVZ of patients after stroke compared to healthy controls. White box indicating quantification area. Scale bar, 25 μm. Quantification of fibrinogen immunoreactivity in the SVZ per area (n = 5 (healthy control), n = 6 (stroke patients, mean ± s.e.m., unpaired Student’s t-test, *P < 0.05). e Representative images of S100β + ependymal cells (green) lining the lateral ventricle and adjacent fibrinogen (red) in the SVZ 5 h after PT (PT Day 0). Scale bar, 40 μm. f CD31 + endothelial cells (green) and fibrinogen (red) in the SVZ and striatum 5 h after PT (PT Day 0). White boxes indicating enlargement of fibrinogen deposition around blood vessels in SVZ (right, bottom) compared to no fibrinogen deposition around blood vessels in the striatum (right, top) after PT. Scale bars, 40 μm, left and 95 µm, enlargement. g GFAP + astrocytes (green) and fibrinogen (red) in the ipsilateral SVZ at different days after PT and uninjured mice. Scale bar, 57 μm. Quantification of GFAP + cells and fibrinogen immunoreactivity in the SVZ per area (n = 3 mice, mean ± s.e.m., one-way ANOVA and Bonferroni’s multiple comparisons test, *P < 0.05, ****P < 0.0001). SVZ subventricular zone.
Fig. 1 Fibrinogen deposition in the SVZ after cortical injury. a GFAP immunostaining (green) around the lesion core (indicated by yellow dotted line) and in the SVZ. White box indicating enlargement of SVZ showing GFAP expression in the adult SVZ 7 days after PT (right) (n = 4 mice). Scale bars, 369 μm, left and 57 µm, enlargement. b Fibrinogen immunostaining (red) in the lesion core and in the SVZ 1 day after PT. White box indicating enlargement of SVZ showing fibrinogen deposition in the SVZ 1 day after PT (right) (n = 4 mice). Scale bars, 428 μm, left and 120 µm, enlargement. c GFAP (green) and fibrinogen (red) immunostainings in the lesion core (left) and in the SVZ (right) 3, 5 and 7 days after stroke (MCAO). White box indicating enlargement of SVZ showing increased GFAP expression colocalizing with fibrinogen (red) deposition in the SVZ 3 days after stroke. Scale bars, 543 μm, left and 50 µm, right (n = 3 mice). d δ-GFAP (green) and fibrinogen (red) immunostainings in the SVZ of patients after stroke compared to healthy controls. White box indicating quantification area. Scale bar, 25 μm. Quantification of fibrinogen immunoreactivity in the SVZ per area (n = 5 (healthy control), n = 6 (stroke patients, mean ± s.e.m., unpaired Student’s t-test, *P < 0.05). e Representative images of S100β + ependymal cells (green) lining the lateral ventricle and adjacent fibrinogen (red) in the SVZ 5 h after PT (PT Day 0). Scale bar, 40 μm. f CD31 + endothelial cells (green) and fibrinogen (red) in the SVZ and striatum 5 h after PT (PT Day 0). White boxes indicating enlargement of fibrinogen deposition around blood vessels in SVZ (right, bottom) compared to no fibrinogen deposition around blood vessels in the striatum (right, top) after PT. Scale bars, 40 μm, left and 95 µm, enlargement. g GFAP + astrocytes (green) and fibrinogen (red) in the ipsilateral SVZ at different days after PT and uninjured mice. Scale bar, 57 μm. Quantification of GFAP + cells and fibrinogen immunoreactivity in the SVZ per area (n = 3 mice, mean ± s.e.m., one-way ANOVA and Bonferroni’s multiple comparisons test, *P < 0.05, ****P < 0.0001). SVZ subventricular zone.CC BY · PubMed Central
Fig. 2 Fibrinogen-induced differentiation of NSPCs into astrocytes. a GFAP + astrocytes (green) in untreated and fibrinogen‐treated adult SVZ-derived NSPCs. Scale bar, 56 μm. Quantification of GFAP + astrocytes. (n = 3, mean ± s.e.m, unpaired Student’s t-test, ***P < 0.001). b Expression of GFAP mRNA in NSPCs. (n = 3, mean ± s.e.m, unpaired Student’s t-test, **P < 0.01). c Immunoblot for GFAP, Aqp4, Aldoc, and GAPDH in NSPCs 2 days after fibrinogen treatment. d Aldh1l1 + (green, top) and Aqp4 + (green, bottom) astrocytes in fibrinogen‐treated adult SVZ-derived NSPC cultures. (n = 3, representative images are shown). Scale bar, 67 μm. e GFAP + astrocytes (green) in fibrinogen‐treated hippocampus-derived NSPC cultures. Scale bar, 104 μm. Quantification of GFAP + astrocytes. (n = 2, performed in duplicate, mean ± s.e.m, unpaired Student’s t-test, *P < 0.05. f S100β (green) and GFAP (red) immunostainings in the SVZ at different timepoints after PT. White boxes indicate enlargement of S100β-GFAP + (right, top) and S100β + GFAP + (right, bottom) cells in the SVZ of uninjured and injured (PT day 3) mice, respectively. Scale bars, 40 μm, left and 7 µm, enlargement. Quantification of S100β + GFAP + cells per area (n = 4 mice, mean ± s.e.m, one-way ANOVA and Bonferroni’s multiple comparisons test, *P < 0.05). g EdU (grey), Thbs4 (green) and GFAP (red) immunostainings in the SVZ at 3 days after PT. White box indicates the enlargement of an EdU + GFAP + Thbs4 + DAPI + cell (right, bottom) in the SVZ 3 days after PT. Scale bar, 25 µm. Quantification of Thbs4 + GFAP + EdU + cells in the SVZ per area. (n = 4 mice, mean ± s.e.m, unpaired Student’s t-test, **P < 0.01). h immunolabeling for Thbs4 (green), S100β (red) and GFAP (gray) in the SVZ at 3 days after PT. White box indicating enlargement of a Thbs4 + S100β + GFAP + DAPI + cell in the SVZ 3 days after PT (n = 4 mice). Scale bar, 25 µm. i Scheme illustrating PT on ancrod-administered WT mice (top). S100β (red) and GFAP (green) immunostainings of the SVZ of ancrod-treated mice 6 days after PT. White boxes indicate enlargement of a S100β + GFAP + (top) and a S100β-GFAP + (bottom) cell in the SVZ of control and fibrinogen-depleted mice, respectively, 6 days after PT. Scale bars, 36 μm, left and 7 µm, enlargement. Quantification of S100β + GFAP + cells in the SVZ per area. (n = 4 mice, unpaired Student’s t-test, *P < 0.05). SVZ, subventricular zone.
Fig. 2 Fibrinogen-induced differentiation of NSPCs into astrocytes. a GFAP + astrocytes (green) in untreated and fibrinogen‐treated adult SVZ-derived NSPCs. Scale bar, 56 μm. Quantification of GFAP + astrocytes. (n = 3, mean ± s.e.m, unpaired Student’s t-test, ***P < 0.001). b Expression of GFAP mRNA in NSPCs. (n = 3, mean ± s.e.m, unpaired Student’s t-test, **P < 0.01). c Immunoblot for GFAP, Aqp4, Aldoc, and GAPDH in NSPCs 2 days after fibrinogen treatment. d Aldh1l1 + (green, top) and Aqp4 + (green, bottom) astrocytes in fibrinogen‐treated adult SVZ-derived NSPC cultures. (n = 3, representative images are shown). Scale bar, 67 μm. e GFAP + astrocytes (green) in fibrinogen‐treated hippocampus-derived NSPC cultures. Scale bar, 104 μm. Quantification of GFAP + astrocytes. (n = 2, performed in duplicate, mean ± s.e.m, unpaired Student’s t-test, *P < 0.05. f S100β (green) and GFAP (red) immunostainings in the SVZ at different timepoints after PT. White boxes indicate enlargement of S100β-GFAP + (right, top) and S100β + GFAP + (right, bottom) cells in the SVZ of uninjured and injured (PT day 3) mice, respectively. Scale bars, 40 μm, left and 7 µm, enlargement. Quantification of S100β + GFAP + cells per area (n = 4 mice, mean ± s.e.m, one-way ANOVA and Bonferroni’s multiple comparisons test, *P < 0.05). g EdU (grey), Thbs4 (green) and GFAP (red) immunostainings in the SVZ at 3 days after PT. White box indicates the enlargement of an EdU + GFAP + Thbs4 + DAPI + cell (right, bottom) in the SVZ 3 days after PT. Scale bar, 25 µm. Quantification of Thbs4 + GFAP + EdU + cells in the SVZ per area. (n = 4 mice, mean ± s.e.m, unpaired Student’s t-test, **P < 0.01). h immunolabeling for Thbs4 (green), S100β (red) and GFAP (gray) in the SVZ at 3 days after PT. White box indicating enlargement of a Thbs4 + S100β + GFAP + DAPI + cell in the SVZ 3 days after PT (n = 4 mice). Scale bar, 25 µm. i Scheme illustrating PT on ancrod-administered WT mice (top). S100β (red) and GFAP (green) immunostainings of the SVZ of ancrod-treated mice 6 days after PT. White boxes indicate enlargement of a S100β + GFAP + (top) and a S100β-GFAP + (bottom) cell in the SVZ of control and fibrinogen-depleted mice, respectively, 6 days after PT. Scale bars, 36 μm, left and 7 µm, enlargement. Quantification of S100β + GFAP + cells in the SVZ per area. (n = 4 mice, unpaired Student’s t-test, *P < 0.05). SVZ, subventricular zone.CC BY · PubMed Central
Fig. 3 Fibrinogen induces astrogliogenesis via the BMP–Id3 axis. a Microarray gene expression profile of NSPCs treated for 12 h with fibrinogen compared to control cells. Heatmap analysis showing genes regulated by a factor of at least 4 between fibrinogen-treated and control NSPCs. (n = 3). b Immunolabeling for phosphorylated Smad1/5/8 (P-Smad1/5/8, red) in fibrinogen-treated hippocampal NSPCs. White boxes indicate enlargement of nuclear P-Smad1/5/8- and P-Smad1/5/8 + cell in untreated and fibrinogen-treated conditions, respectively. Scale bar, 46 μm. Quantification of nuclear P-Smad1/5/8. (n = 2, experiments performed in duplicates (mean ± s.e.m., unpaired Student’s t-test, ***P < 0.001). c Immunoblot for P-Smad1/5/8 and Smad1 in NSPCs pretreated with a BMP receptor inhibitor before fibrinogen stimulation. BMP-2 served as positive control. d GFAP + astrocytes in NSPC cultures pretreated with a BMP receptor inhibitor 1 h before fibrinogen treatment 2 days after initiation of differentiation. Scale bar, 125 μm. Quantification of GFAP + astrocytes. (n = 5, (mean ± s.e.m, one-way ANOVA and Bonferroni’s multiple comparisons test, **P < 0.01, ***P < 0.001, ****P < 0.0001). e GFAP + astrocytes (green) in fibrinogen-treated Id3−/− and WT NSPCs cultures after 2 days on poly‐D‐lysine. Scale bar, 72 μm. Quantification of GFAP + astrocytes. (n = 4, WT; n = 3, Id3−/− cells, mean ± s.e.m, unpaired Student’s t-test, *P < 0.05). f Experimental setup for photothrombosis on Nestin-CreERT2::Rosa26-yfp mice. TAM: tamoxifen (right, top). Id3 (red) and YFP (green) immunostainings in the SVZ of uninjured mice and of ancrod-treated mice compared to control WT mice 1 day after PT. The white boxes indicate the enlargement of an Id3 + YFP + (right, top) and an Id3-YFP + (right, bottom) cell in the SVZ of control mice and fibrinogen-depleted mice, respectively, 1 day after PT. Scale bars, 30 μm, left and 8 µm, enlargement. Quantification of Id3 + YFP + cells in the SVZ per area. (n = 4 uninjured mice, n = 4 control mice after PT, n = 3 ancrod mice after PT, unpaired Student’s t-test, *P < 0.05).
Fig. 3 Fibrinogen induces astrogliogenesis via the BMP–Id3 axis. a Microarray gene expression profile of NSPCs treated for 12 h with fibrinogen compared to control cells. Heatmap analysis showing genes regulated by a factor of at least 4 between fibrinogen-treated and control NSPCs. (n = 3). b Immunolabeling for phosphorylated Smad1/5/8 (P-Smad1/5/8, red) in fibrinogen-treated hippocampal NSPCs. White boxes indicate enlargement of nuclear P-Smad1/5/8- and P-Smad1/5/8 + cell in untreated and fibrinogen-treated conditions, respectively. Scale bar, 46 μm. Quantification of nuclear P-Smad1/5/8. (n = 2, experiments performed in duplicates (mean ± s.e.m., unpaired Student’s t-test, ***P < 0.001). c Immunoblot for P-Smad1/5/8 and Smad1 in NSPCs pretreated with a BMP receptor inhibitor before fibrinogen stimulation. BMP-2 served as positive control. d GFAP + astrocytes in NSPC cultures pretreated with a BMP receptor inhibitor 1 h before fibrinogen treatment 2 days after initiation of differentiation. Scale bar, 125 μm. Quantification of GFAP + astrocytes. (n = 5, (mean ± s.e.m, one-way ANOVA and Bonferroni’s multiple comparisons test, **P < 0.01, ***P < 0.001, ****P < 0.0001). e GFAP + astrocytes (green) in fibrinogen-treated Id3−/− and WT NSPCs cultures after 2 days on poly‐D‐lysine. Scale bar, 72 μm. Quantification of GFAP + astrocytes. (n = 4, WT; n = 3, Id3−/− cells, mean ± s.e.m, unpaired Student’s t-test, *P < 0.05). f Experimental setup for photothrombosis on Nestin-CreERT2::Rosa26-yfp mice. TAM: tamoxifen (right, top). Id3 (red) and YFP (green) immunostainings in the SVZ of uninjured mice and of ancrod-treated mice compared to control WT mice 1 day after PT. The white boxes indicate the enlargement of an Id3 + YFP + (right, top) and an Id3-YFP + (right, bottom) cell in the SVZ of control mice and fibrinogen-depleted mice, respectively, 1 day after PT. Scale bars, 30 μm, left and 8 µm, enlargement. Quantification of Id3 + YFP + cells in the SVZ per area. (n = 4 uninjured mice, n = 4 control mice after PT, n = 3 ancrod mice after PT, unpaired Student’s t-test, *P < 0.05).CC BY · PubMed Central
Fig. 4 Fibrinogen αC domain requirement for NSPC differentiation into astrocytes. a Immunoblot for P-Smad1/5/8 and Smad1 in NSPCs pretreated with an increasing concentration of Noggin before fibrinogen stimulation. BMP-2 served as positive control. b Scheme illustrating fibrinogen fractions isolated from plasma. Human Des-αC-fibrinogen lacks most of the residues of the C-terminus of the Aα chain including the RGD sequence. c Immunoblot for P-Smad1/5/8 and total Smad1 protein expression in NSPCs 2 days after fibrinogen or Des-αC-fibrinogen treatment. Values are mean of n = 3 independent experiments. d GFAP + astrocytes in fibrinogen- and Des-αC-fibrinogen-treated NSPC cultures 2 days after initiation of differentiation. Scale bar, 125 μm. Quantification of GFAP + astrocytes derived from fibrinogen- or Des-αC-fibrinogen-treated NSPCs. Results are from four independent experiments (mean ± s.e.m, one-way ANOVA and Bonferroni’s multiple comparisons test, ****P < 0.0001). e Active β1-integrin (green) immunostaining in WT NSPCs treated for 15 min with AF594-fibrinogen (red). Scale bar, 2 μm. Representative images of two independent experiments are shown. f GFAP + astrocytes in untreated and fibrinogen-treated NSPC cultures pretreated with the integrin-blocking RGDS or the control PDEA peptides for 2 days. Scale bar, 60 μm. Quantification of GFAP + astrocytes derived from untreated and fibrinogen-treated NSPCs pretreated with the PDEA (control) and RGDS peptides. Results from three independent experiments performed in duplicates are shown (mean ± s.e.m, one-way ANOVA and Bonferroni’s multiple comparisons test, *P < 0.05, **P < 0.01, ns not significant).
Fig. 4 Fibrinogen αC domain requirement for NSPC differentiation into astrocytes. a Immunoblot for P-Smad1/5/8 and Smad1 in NSPCs pretreated with an increasing concentration of Noggin before fibrinogen stimulation. BMP-2 served as positive control. b Scheme illustrating fibrinogen fractions isolated from plasma. Human Des-αC-fibrinogen lacks most of the residues of the C-terminus of the Aα chain including the RGD sequence. c Immunoblot for P-Smad1/5/8 and total Smad1 protein expression in NSPCs 2 days after fibrinogen or Des-αC-fibrinogen treatment. Values are mean of n = 3 independent experiments. d GFAP + astrocytes in fibrinogen- and Des-αC-fibrinogen-treated NSPC cultures 2 days after initiation of differentiation. Scale bar, 125 μm. Quantification of GFAP + astrocytes derived from fibrinogen- or Des-αC-fibrinogen-treated NSPCs. Results are from four independent experiments (mean ± s.e.m, one-way ANOVA and Bonferroni’s multiple comparisons test, ****P < 0.0001). e Active β1-integrin (green) immunostaining in WT NSPCs treated for 15 min with AF594-fibrinogen (red). Scale bar, 2 μm. Representative images of two independent experiments are shown. f GFAP + astrocytes in untreated and fibrinogen-treated NSPC cultures pretreated with the integrin-blocking RGDS or the control PDEA peptides for 2 days. Scale bar, 60 μm. Quantification of GFAP + astrocytes derived from untreated and fibrinogen-treated NSPCs pretreated with the PDEA (control) and RGDS peptides. Results from three independent experiments performed in duplicates are shown (mean ± s.e.m, one-way ANOVA and Bonferroni’s multiple comparisons test, *P < 0.05, **P < 0.01, ns not significant).CC BY · PubMed Central
Fig. 5 Fibrinogen-induced SVZ astrocytes add to cortical scar. a Representation of the different lesion regions quantified by immunoreactivity. b Fibrinogen deposition (red) and GFAP + astrocytes in the brain of fibrinogen-depleted mice (Ancrod) compared to controls (NaCl) at 6 days after PT (left). Yellow dotted line delineates the lesion area. The white boxes indicate the enlargement of the lesion region quantified for GFAP (right, top) and CSPGs (right, bottom) immunoreactivities. Quantifications of GFAP and CSPG immunoreactivities in the different lesion regions (n = 4 mice, mean ± s.e.m, one-way ANOVA and Bonferroni’s multiple comparisons test, *P < 0.05). c Immunolabeling for Thbs4 (green) and GFAP (red) in the lesion area of ancrod and control mice at 6 days after PT. Yellow dotted lines delineate the penumbra. The white boxes indicate the enlargement of a Thbs4 + GFAP + cell (top, right) in controls and Thbs4 + GFAP- cell in ancrod mice (right, bottom). Quantification of Thbs4 + GFAP + astrocytes in the penumbra of ancrod and control mice (n = 4 mice, mean ± s.e.m, unpaired Student’s t-test, *P < 0,05). d Experimetal setup for ancrod-administered Nestin-CreERT2::Rosa26-yfp mice. TAM: tamoxifen (top). YFP (green), Thbs4 (red) and GFAP (blue) immunostainings in the lesion area of ancrod and control mice at 10 days after PT. Yellow dotted lines delineate the lesion area. The white boxes indicate the enlargement of an YFP + Thbs4 + GFAP + cell in control and YFP + Thbs4 + GFAP- cell in ancrod mice. Quantifications of YFP + Thbs4 + GFAP + astrocytes (left) and YFP + Thbs4 + cells (right) in the penumbra of ancrod and control mice (n = 2 control mice, n = 3 ancrod mice, unpaired, one-tailed Student’s t-test, *P < 0,05, ns, not significant). SVZ subventricular zone.
Fig. 5 Fibrinogen-induced SVZ astrocytes add to cortical scar. a Representation of the different lesion regions quantified by immunoreactivity. b Fibrinogen deposition (red) and GFAP + astrocytes in the brain of fibrinogen-depleted mice (Ancrod) compared to controls (NaCl) at 6 days after PT (left). Yellow dotted line delineates the lesion area. The white boxes indicate the enlargement of the lesion region quantified for GFAP (right, top) and CSPGs (right, bottom) immunoreactivities. Quantifications of GFAP and CSPG immunoreactivities in the different lesion regions (n = 4 mice, mean ± s.e.m, one-way ANOVA and Bonferroni’s multiple comparisons test, *P < 0.05). c Immunolabeling for Thbs4 (green) and GFAP (red) in the lesion area of ancrod and control mice at 6 days after PT. Yellow dotted lines delineate the penumbra. The white boxes indicate the enlargement of a Thbs4 + GFAP + cell (top, right) in controls and Thbs4 + GFAP- cell in ancrod mice (right, bottom). Quantification of Thbs4 + GFAP + astrocytes in the penumbra of ancrod and control mice (n = 4 mice, mean ± s.e.m, unpaired Student’s t-test, *P < 0,05). d Experimetal setup for ancrod-administered Nestin-CreERT2::Rosa26-yfp mice. TAM: tamoxifen (top). YFP (green), Thbs4 (red) and GFAP (blue) immunostainings in the lesion area of ancrod and control mice at 10 days after PT. Yellow dotted lines delineate the lesion area. The white boxes indicate the enlargement of an YFP + Thbs4 + GFAP + cell in control and YFP + Thbs4 + GFAP- cell in ancrod mice. Quantifications of YFP + Thbs4 + GFAP + astrocytes (left) and YFP + Thbs4 + cells (right) in the penumbra of ancrod and control mice (n = 2 control mice, n = 3 ancrod mice, unpaired, one-tailed Student’s t-test, *P < 0,05, ns, not significant). SVZ subventricular zone.CC BY · PubMed Central
Fig. 6 Working model for the role of fibrinogen on SVZ NSPCs in CNS disease. In the healthy brain, NSPCs of the SVZ continuously generate mobile DCX+ neuroblasts that migrate through the rostral migratory stream to the olfactory bulb to become newborn neurons. Cortical injury results in increased SVZ vasculature permeability and fibrinogen deposition into the SVZ stem cell niche environment. Fibrinogen activates BMP receptor signaling via its αC domain inducing NSPC differentiation into neuroprotective astrocytes, which migrate towards the cortical lesion area and secrete Thbs4. Local provisional fibrinogen thus activates BMP signaling in NSPCs inducing their differentiation into astrocytes at sites of vascular permeability in the CNS. CSF cerebrospinal fluid, NSPCs neural stem/precursor cells, RGD Arg–Gly-Asp sequence (integrin binding site), SVZ subventricular zone. The Astrocyte image was adapted from http://togotv.dbcls.jp/ja/togopic.2011.17.html, under Creative Commons Attribution 4.0 International (CC BY 4.0) license. The original astrocyte image was designed by Hiromasa Ono. The Brain image was adapted from https://icon-icons.com/de/symbol/Gehirn/39333, under Creative Commons Attribution 4.0 International (CC BY 4.0) license. The original brain image was designed by Lorc, Delapouite & contributors.
Fig. 6 Working model for the role of fibrinogen on SVZ NSPCs in CNS disease. In the healthy brain, NSPCs of the SVZ continuously generate mobile DCX+ neuroblasts that migrate through the rostral migratory stream to the olfactory bulb to become newborn neurons. Cortical injury results in increased SVZ vasculature permeability and fibrinogen deposition into the SVZ stem cell niche environment. Fibrinogen activates BMP receptor signaling via its αC domain inducing NSPC differentiation into neuroprotective astrocytes, which migrate towards the cortical lesion area and secrete Thbs4. Local provisional fibrinogen thus activates BMP signaling in NSPCs inducing their differentiation into astrocytes at sites of vascular permeability in the CNS. CSF cerebrospinal fluid, NSPCs neural stem/precursor cells, RGD Arg–Gly-Asp sequence (integrin binding site), SVZ subventricular zone. The Astrocyte image was adapted from http://togotv.dbcls.jp/ja/togopic.2011.17.html, under Creative Commons Attribution 4.0 International (CC BY 4.0) license. The original astrocyte image was designed by Hiromasa Ono. The Brain image was adapted from https://icon-icons.com/de/symbol/Gehirn/39333, under Creative Commons Attribution 4.0 International (CC BY 4.0) license. The original brain image was designed by Lorc, Delapouite & contributors.CC BY · PubMed Central

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Metadata

Authors
Pous, L., Deshpande, S. S., Nath, S., Mezey, S., Malik, S. C., Schildge, S., Bohrer, C., Topp, K., Pfeifer, D., Fernández-Klett, F., Doostkam, S., Galanakis, D. K., Taylor, V., Akassoglou, K., & Schachtrup, C.
ORCID
Taylor, Verdon
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-01-31
Volume
11
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-020-14466-y
PMC
PMC6994610
Cited by
81
References
12
Language
en
Licence

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