PMCID
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
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Arrowheads indicate capsule macs.(B and C) Representative images showing expression of indicated markers at the portal triad by confocal microscopy.
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
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Insets on right.
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PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
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Scale bars, 100 μm.
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
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Insets scale bars, 50 μm (B).
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
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Scale bars, 150 μm.
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
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Insets scale bars, 75 μm (C).(D) Human bile-duct LAMs identified using the murine bile-duct LAM gene signature and the signature finder algorithm (Pont et al., 2019).(E) Human LAM signature from scRNA-seq mapped onto the Visium zonation data, healthy (purple), steatotic (yellow).(F) Expression of indicated markers by confocal microscopy.
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Insets on right.
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PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Scale bars, 150 μm.
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PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
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Insets scale bars, 75 μm.(G and H) Expression of indicated genes in healthy (G) and steatotic (H) human liver.
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
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Insets on right.
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PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Images are representative of 2 patients per condition.(I) Mice were fed a western diet (WD) or standard diet (SD) for 36 weeks to induce NAFLD and Visium analysis was performed.
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PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Analysis is pooled from 1 liver slice from the SD condition and 3 liver slices from the WD condition.
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PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Zonation pattern and H&E staining (left) and LAM and KC location (right).(J) Heatmap showing DEGs between LAMs from SD (purple) and WD (yellow) fed mice (24 + 36 weeks pooled).(K) LAMs were FACS-purified from the liver of mice fed the SD or WD for 24 weeks (with removal of capsule prior to digestion), RNA was isolated and expression of indicated genes was assessed by qPCR relative to β-actin.
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PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
p < 0.05, p < 0.0001, Student’s t test.
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PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Data are pooled from 2 independent experiments with n = 7–10 mice per group.
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PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Images from (A–C and F) are representative of 4–5 patients per condition.
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
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PV, portal vein; CV, central vein.
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
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See also Figure S8 and Table S2.Figure S8Evolutionarily conserved signals regulate LAM and KC development, related to Figures 5 and 7(A) Confocal microscopy of healthy human liver showing expression of indicated markers.
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Scale bars, 200 μm.(B and C) Expression of conserved human-murine bile-duct LAM signature in human (B) and mouse (C) hepatic myeloid cells.(D) Proportion of indicated myeloid cell populations as a % of total myeloid cells in human liver biopsies profiled by scRNA-seq when divided based on presence of steatosis.(E) Mice were fed a western diet (WD) or standard diet (SD) for 36 weeks to induce NAFLD and Visium analysis was performed.
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PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Analysis is pooled from 1 liver slice from the SD condition and 3 liver slices from the WD condition.
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Shown are cluster and sample annotations.(F) Zonation of all cell types from Figure S5J in murine NAFLD map (SD&WD).(G) Differential NicheNet highlighting prioritized conserved (human-mouse) ligand-receptor (LR) pairs between indicated macs and their niche cells.
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
LR pairs are grouped according to the niche cell type with highest ligand expression.(H) Expression of ALK1 (ACVRL1), BMP9 (GDF2), and BMP10 in human, mouse, and macaque livers where both KCs and stellate cells were profiled.(I) Livers were harvested from Clec4f-CrexAcvrl1 mice or Acvrl1 controls and KCs examined (top) and quantified (middle) using VSIG4 expression.
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Expression of indicated KC markers by mac populations in Clec4f-CrexAcvrl1 or Acvrl1 control mice (bottom).
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Data are pooled from 2 independent experiments with n = 14 per group.
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PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Student’s t test.
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
p < 0.0001.(J) Expression of CD31 (ECs), DESMIN (stromal cells), F4/80 (Macs), and EPCAM (cholangiocytes) by confocal microscopy in Fcgr1-CrexAcvrl1 mice and Acvrl1 controls.
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PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
PV, portal vein; CV, central vein.
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PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Images are representative of 2 mice per group.
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
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Conserved and unique features of KCs across species, related to Figure 4 (A and B) Expression of human-murine KC signature genes across cell types in mouse (A) and human (B). (
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
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C) Unbiased identification of KCs in mouse and human using the human-murine KC signature and the signature finder algorithm (Pont et al., 2019). (
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
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D–H) Annotated UMAPs from indicated species and expression of top KC-specific genes compared with other cells per species. (
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
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I) Expression of previously identified core murine transcription factors (Bonnardel et al., 2019) by KCs across species. (
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
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J) Venn diagram showing convergence and divergence of expression of top 50 KC genes per species across species, see Table S9 for genes lists per species. (
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
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K) Top DEPs (identified with cross reactive human antibodies) in the pig CITE-seq data. (
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
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L) Expression of VSIG4 in the porcine liver by confocal microscopy. (
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
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M) Expression of VSIG4, CD68 (protein), and CD5L (mRNA) in macaque liver.
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
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PV, portal vein; HA, hepatic artery; BD, bile duct.
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
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All images are representative of 2 livers. (
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
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N and O) Conserved expression of indicated genes across CD45 (N) and CD45 (O) cell types and species.
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
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LAMs are found at the bile duct in the healthy liver, but at zones of steatosis in the obese liver (A) Expression of indicated markers at the capsule of the healthy human liver (H14) by confocal microscopy.
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Scale bars, 20 μm.
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PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Arrowheads indicate capsule macs. (
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PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
B and C) Representative images showing expression of indicated markers at the portal triad by confocal microscopy.
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Insets on right.
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Scale bars, 100 μm.
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Insets scale bars, 50 μm (B).
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Scale bars, 150 μm.
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Insets scale bars, 75 μm (C). (
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PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
D) Human bile-duct LAMs identified using the murine bile-duct LAM gene signature and the signature finder algorithm (Pont et al., 2019). (
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PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
E) Human LAM signature from scRNA-seq mapped onto the Visium zonation data, healthy (purple), steatotic (yellow). (
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
F) Expression of indicated markers by confocal microscopy.
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PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Insets on right.
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Scale bars, 150 μm.
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Insets scale bars, 75 μm. (
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
G and H) Expression of indicated genes in healthy (G) and steatotic (H) human liver.
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PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Insets on right.
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Images are representative of 2 patients per condition. (
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
I) Mice were fed a western diet (WD) or standard diet (SD) for 36 weeks to induce NAFLD and Visium analysis was performed.
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Analysis is pooled from 1 liver slice from the SD condition and 3 liver slices from the WD condition.
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Zonation pattern and H&E staining (left) and LAM and KC location (right). (
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
J) Heatmap showing DEGs between LAMs from SD (purple) and WD (yellow) fed mice (24 + 36 weeks pooled). (
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
K) LAMs were FACS-purified from the liver of mice fed the SD or WD for 24 weeks (with removal of capsule prior to digestion), RNA was isolated and expression of indicated genes was assessed by qPCR relative to β-actin.
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
p < 0.05, p < 0.0001, Student’s t test.
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Data are pooled from 2 independent experiments with n = 7–10 mice per group.
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Images from (A–C and F) are representative of 4–5 patients per condition.
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
PV, portal vein; CV, central vein.
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
See also Figure S8 and Table S2.
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Evolutionarily conserved signals regulate LAM and KC development, related to Figures 5 and 7 (A) Confocal microscopy of healthy human liver showing expression of indicated markers.
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Scale bars, 200 μm. (
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
B and C) Expression of conserved human-murine bile-duct LAM signature in human (B) and mouse (C) hepatic myeloid cells. (
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
D) Proportion of indicated myeloid cell populations as a % of total myeloid cells in human liver biopsies profiled by scRNA-seq when divided based on presence of steatosis. (
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
E) Mice were fed a western diet (WD) or standard diet (SD) for 36 weeks to induce NAFLD and Visium analysis was performed.
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Analysis is pooled from 1 liver slice from the SD condition and 3 liver slices from the WD condition.
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Shown are cluster and sample annotations. (
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
F) Zonation of all cell types from Figure S5J in murine NAFLD map (SD&WD). (
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
G) Differential NicheNet highlighting prioritized conserved (human-mouse) ligand-receptor (LR) pairs between indicated macs and their niche cells.
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
LR pairs are grouped according to the niche cell type with highest ligand expression. (
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
H) Expression of ALK1 (ACVRL1), BMP9 (GDF2), and BMP10 in human, mouse, and macaque livers where both KCs and stellate cells were profiled. (
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
I) Livers were harvested from Clec4f-CrexAcvrl1 mice or Acvrl1 controls and KCs examined (top) and quantified (middle) using VSIG4 expression.
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Expression of indicated KC markers by mac populations in Clec4f-CrexAcvrl1 or Acvrl1 control mice (bottom).
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Data are pooled from 2 independent experiments with n = 14 per group.
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Student’s t test.
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
p < 0.0001. (
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
J) Expression of CD31 (ECs), DESMIN (stromal cells), F4/80 (Macs), and EPCAM (cholangiocytes) by confocal microscopy in Fcgr1-CrexAcvrl1 mice and Acvrl1 controls.
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
PV, portal vein; CV, central vein.
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Images are representative of 2 mice per group.
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Given the altered localization of KCs in the healthy murine versus human liver and LAMs in the healthy versus steatotic liver of mice and humans, we next sought to investigate how the cells of the mac niches differed in these settings.
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
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Analysis of CD45 cells in the human liver identified similar (sub)populations of ECs, SCs, and hepatocytes as observed in the healthy mouse liver (Figures 6A and 6B; Table S3).
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PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
However, while the 100-plex MICS analysis detected a second subset of portal fibroblasts expressing DESMIN (Figure S6H), we did not detect these cells in our UMAP, likely due to difficulties detecting DESMIN with snRNA-seq.
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PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
No significant differences were found in terms of localization of the identified CD45 cells that could explain the altered location of KCs compared with the mouse (Figures 6C and 6D).
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PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
With this in mind, we next utilized NicheNet to examine potential ligand-receptor pairs between KCs and CD45 cells present only in the human that could regulate KC location.
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
This analysis identified CCL23 and CCL14 expression by LSECs and CCL16 by hepatocytes that binds to CCR1 expressed by human KCs but not murine KCs (Figure 6E).
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Crucially, these ligands were preferentially located peri-centrally (Figure 6F) and thus represent interesting targets for further study regarding the potential regulation of KC location in the human liver.
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PMC8809252
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Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Figure 6Macrophage niche cells may regulate macrophage locations in healthy versus steatotic liver(A) UMAP of human CD45 cells (15,481 cells/nuclei) isolated from Figure 4B and re-clustered with scVI.(B) Top DEGs between cell types identified.(C) Indicated cell signatures from sc/snRNA-seq mapped onto the Visium zonation data, healthy (top), steatotic (bottom).(D) Molecular Cartography localizing distinct CD45 cells.(E) Circos plot showing NicheNet predicted ligand-receptor pairs between KCs and LSECs, HSCs and hepatocytes uniquely expressed in the human liver (left) and UMAPs showing normalized expression of indicated chemokines in the human liver (right) and CCR1/Ccr1 in the human and murine NAFLD liver (bottom).(F) Zonation of indicated genes in the healthy and steatotic human liver.(G) UMAP of murine NAFLD (SD and WD) stromal cells (4,025 cells/nuclei) isolated from Figure S5J and re-clustered with scVI (left) and proportions of each cell type in SD- and WD-fed mice (right).(H) Top DEGs between cell types.(I) Mice were fed a western diet (WD) or standard diet (SD) for 36 weeks to induce NAFLD, and Visium analysis was performed.
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Analysis is pooled from 1 liver slice from the SD condition and 3 liver slices from the WD condition.
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Zonation of Ccl2 fibroblasts and fibroblasts in SD- and WD-fed mice.
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PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
See also Tables S3 and S10.
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
Macrophage niche cells may regulate macrophage locations in healthy versus steatotic liver (A) UMAP of human CD45 cells (15,481 cells/nuclei) isolated from Figure 4B and re-clustered with scVI. (
|
PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
B) Top DEGs between cell types identified. (
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PMC8809252
|
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.
|
C) Indicated cell signatures from sc/snRNA-seq mapped onto the Visium zonation data, healthy (top), steatotic (bottom). (
|
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