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Supplemental Figures 1 SUPPLEMENTARY MATERIALS: 2 3 Supplemental figures 4 1 Control lung IPF lung (perivascular space) (fbroblast foci) PRRX1 PRRX1 PRRX1 PRRX1 aB VIM b ACTA2 d VIM e ACTA2 PRRX1 PRRX1 c CD45 f CD45 Supplemental Figure 1 5 Supplemental Figure S1: Co-expression of PRRX1 with Vimentin and ACTA2 in control 6 and IPF lungs by immunochemistry. 7 (a-c) Representative immunohistochemistry images (n=3 per group) in control lung showing 8 PRRX1 staining (Brown Chromogen, nuclear staining) in perivascular space with (a) Vimentin 9 (Red chromogen), (b) ACTA2 (Red chromogen) and (c) CD45 (Red chromogen). Note that 10 PRRX1 positive cells (arrow) were Vimentine positive (a) but ACTA2 (b) and CD45 negative 11 (c). Insert in (a): high magnification of the black dashed box in the main left panel showing a 12 double positive PRRX1 (brown nuclear staining, outlined with dashed white line) and Vimentin 13 (red cytoplasmic staining) cell. Insert in (c): high magnification of the black dashed box in the 14 main bottom panel showing a PRRX1 (brown nuclear staining) positive but CD45 negative cell 15 (arrow) as well as a CD45 (red cytoplasmic staining) positive but PRRX1 negative cell 16 (arrowhead). (d-f) Representative immunohistochemistry images (n=3 per group) showing 17 PRRX1 staining (Brown Chromogen, nuclear staining) in IPF fibroblast foci with (d) Vimentin 18 (Red chromogen), (e) ACTA2 (Red chromogen) and (f) CD45 (Red chromogen). Note that 19 PRRX1 positive cells were Vimentin positive (see black arrow in (d)) but only some were 20 ACTA2 positive (arrow and dashed box in (e)). PRRX1pos ACTA2neg cells were also present 21 (see arrowhead in (e)). All PRRX1pos cell populations were also CD45 negative (f). Insert in 22 (d): high magnification of the black dashed box in the main left panel showing a double positive 23 PRRX1 (brown nuclear staining, see black arrow) and Vimentin (red cytoplasmic staining) 24 cells. Note that the epithelium is negative for both markers. Panel in (e): high magnification of 25 the black dashed box in the main right panel showing a double positive PRRX1 (brown nuclear 26 staining, see black arrow) and ACTA2 (red cytoplasmic staining) cell. PRRX1pos ACTA2neg cells 27 were also present (see arrowhead). Right panel in (f): high magnification of the black dashed 28 box in the main left bottom panel showing a PRRX1 (brown nuclear staining) positive but CD45 29 negative cell (arrow) and a CD45pos (red cytoplasmic staining) positive but PRRX1neg cell 30 (arrowhead). Nuclei were counterstained with hematoxylin in all panels. Abbreviations: Vim 31 (Vimentin), Pos (positive), neg (negative). (Scale bar: 50µm in (a-b), 80μm in (c) and 25µm in 32 high magnification (a and c); 80µm in (d-f) and 40µm in high magnification (d-f)). 33 2 Supplemental Figure 2 PRRX1 mRNA expression UMAP2 a Aberrant Basaloid AT1 AT2 Bcell Plasmacytoid B Cell Basal Eptih. Cell Ciliated Eptih. Cell Club Eptih. Cell DCs A DCs B DCs C Langerhans DCs pDCs Fibroblast Goblet Innate Lymphoid A Epithelial Immune Innate Lymphoid B Stromal Ionocyte Lymphatic UMAP1 Macrophage Alveolar Macrophage Mast Cell Mesothelial Cell Monocyte Non Classical Monocyte Myofbroblast NK Cell Pericyte PNEC Smooth muscle Cell TCelll Cyttooxic T Cell PRRX1 Regulatory T Cell IPF VE_arterial Control VE Capillary A VE Capillary B VE Peribronchial VE Veinous UMAP2 b PRRX1 mRNA expression AT1 AT2 Bcell Basal Eptih. Cell cDCs Ciliated Eptih. Cells Differentiat. Cilaited Eptih. Cell Endothelial cell Fibroblast HAS1 High Fibroblast KRT5-/KRT17+ Eptih. Cell Epithelial Lymphatic Endothelial cell Immune Stromal Macrophages Mast cell UMAP1 Mesothelial Cell Monocyte MUC5AC+ High Eptih. Cell MUC5B+ Eptih. Cell Myofbroblast NK pDCs Plasmacytoid B Cell PLIN2+ Fibroblast Proliferating Epith. Cell Proliferating Macrophage ILD Proliferating T Cell Control SCGB3A2+ Eptih. Cell SCGB3A2+ SCGB1A1+ Eptih. Cell PRRX1 Smooth muscle Cell TCell Transitional AT2 34 Supplemental Figure S2 : PRRX1 expression profiles at single cell resolution using the 35 “IPF Cell Atlas” web database (http://ipfcellatlas.com/). 36 (a-b) UMAP plots describing the distribution of PRRX1 expressing cells in different lung cell 37 lineage clusters were drawn with UMAP Explorer (upper part) using (a) Kropski’s and (b) 38 Misharin’s datasets. The labeling of each cell cluster (including all samples) are shown on the 39 left and PRRX1 relative expression in those clusters is shown on the right. In the lower part, 40 violin plots visualizing PRRX1 mRNA expression in each cell type stratified by disease states 41 (control lung cell types in blue (a-b) and IPF (a) or ILD (b) ones in red) were drawn with Gene 42 Explorer using (a) Kropski’s dataset and in (b) Misharin’s dataset. Note that PRRX1 mRNA 43 expression was associated with stromal clusters in both datasets (dashed lines in the upper 44 part and labels in bold font in the lower part). Abbreviations: AT1 (alveolar type 1 epithelial 45 cell), AT2 (alveolar type 2 epithelial cell), Epith. (epithelial), B Cell (B lymphocyte), T Cell (T 46 lymphocyte), DCs (DenDritic cells), pDCs (plasmacytoid DenDritic cells), NK Cell (Natural Killer 47 cell), PNEC (pulmonary neuroendocrine cell), VE (vascular enDothelium), ILD (interstitial lung 48 Disease). 49 3 a b Control IPF Control TGF-β1 PGE2 PRRX1 PRRX1 GAPDH GAPDH Total PRRX1 Total PRRX1 2.5 100 $ $ H H D D 2.0 ) l AP ) l a AP a s /G s /G 1.5 1 ba 1 ( X 10 ba ( X o i t RR o i a t 1.0 RR P r a Basal P r e v i e t v i Basal 0.5 a l t e a 1 l r e r 0.0 Control IPF Control IPF Control IPF Control IPF l a s H a O t B PRRX1 E PHAL DAPI 1 2 β E F G G P T TGFβ11ng/ml PGE2 100nM 0.6 1.0 ** 1.0 1.0 e e e 0.8 ** e * v v c * c e i 0.8 i I t t I v i en P a en a P t ** l l A 0.4 A a 0.8 sc e 0.8 e sc l D D r e r e 0.6 r e r r to to e 0.6 e uo uo e c c e e f f v n i v i n i i c 1 0.4 p 1 0.6 e p 0.6 at e n i at l X l X 0.2 c a c a p e e e r s R r s D c a D RR e R e s r P D 0.2 0.4 o P r o t e t o o r 0.4 o 0.4 u t u l o l f f u l 0.0 0.0 f 1 Basal TGFβ1 Basal TGFβ1 EtOH PGE2 EtOH PGE2 1 X 1 0.2 0.2 X 0.2 X R R R R Control IPF Control IPF R P R P P 0.0 0.0 0.0 EtOH PGE2 EtOH PGE2 Heparin FGF2 Heparin Basal TGFb Basal TGFb 10-7M 10-7M Supplemental1ng/mL Figure1ng/mL 3 20ng/mL Control IPF Control IPF Control 50 Supplemental Figure S3: Regulation of PRRX1 protein expression by growth factors as 51 assayed by immunoblots and immunofluorescence. 52 (a) Upper part: immunoblot showing PRRX1 expression in control and IPF primary Human 53 lung fibroblasts stimulated 48h with TGF-β1. GAPDH was used as loading control. Middle 54 panel: quantification of PRRX1 relative expression to GAPDH in control (circle) and IPF 55 (square) lung fibroblasts stimulated for 48h with TGF-β1 compared to basal condition (red 56 dashed line). Lower part: representative immunofluorescence images (n=7 per group) of 57 PRRX1 expression (red) in control and IPF lung fibroblasts at basal level or stimulated for 48h 58 with TGF-β1 (1ng/ml). DAPI was used as loading control. Actin fibers (green) were stained 59 with Phalloidin. The quantification of PRRX1 relative expression to DAPI in control (circle) and 60 IPF (square) lung fibroblasts at basal level or stimulated 48h with TGF-β1 is displayed as dot 61 plot with median on the lower panel. (b) Upper part: immunoblot showing PRRX1 expression 62 in control and IPF primary Human lung fibroblasts stimulated 48h with PGE2. GAPDH was 63 used as loading control. Middle panel: quantification of PRRX1 relative expression to GAPDH 64 in control (circle) and IPF (square) lung fibroblasts stimulated for 48h with PGE2 compared to 65 basal condition (red dashed line). Lower part: representative immunofluorescence images 66 (n=7 per group) of PRRX1 expression (red) in control and IPF lung fibroblasts stimulated for 67 48h with EtOH or PGE2 (100nM). DAPI was used as loading control. Actin fibers (green) were 68 stained with Phalloidin. The quantification of PRRX1 relative expression to DAPI in control 69 (circle) and IPF (square) lung fibroblasts stimulated for 48h with EtOH or PGE2 is displayed 70 as dot plot on the bottom. (c) Upper part: immunoblot showing PRRX1 expression in control 71 and IPF primary Human lung fibroblasts stimulated 48h with FGF2. GAPDH was used as 72 loading control. Middle panel: quantification of PRRX1 relative expression to GAPDH in control 73 (circle) and IPF (square) lung fibroblasts stimulated for 48h with FGF2 compared to basal 74 condition (red dashed line). Lower part: representative immunofluorescence images (n=7 per 75 group) of PRRX1 expression (red) in control and IPF lung fibroblasts stimulated for 48h with 76 Heparin or FGF2 (20ng/ml). DAPI was used as loading control. Actin fibers (green) were 77 stained with Phalloidin. The quantification of PRRX1 relative expression to DAPI in control 78 (circle) and IPF (square) lung fibroblasts stimulated 48h with Heparin or FGF2 is displayed as 79 dot plot with median on the bottom (Scale bar: 50µm), (Abbreviations: PhalloiDin (PHAL)).
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