Figure 7: TRMs shape the tissue-protective fibrotic response.

a. UMAP plot of pancreas podoplanin⁺ fibroblasts sorted from IgG+PBS or CSF1 Ab+CLD treated mice rested for 10 days then administered 6 hourly i.p. injections of Cer every other day for one week. b. UMAP plots displaying Podoplanin, Pdgfra, Ly6c1, Acta2 and Col8a1 expression in podoplanin⁺ pancreas fibroblasts of IgG+PBS and CSF1 Ab+CLD-treated mice as in a. c. UMAP plot showing the classification of fibroblast clusters into Ly6C⁺ iFib, αSMA⁺ myFib and MHCII⁺ apFib subtypes in pancreas podoplanin⁺ fibroblasts of IgG+PBS and CSF1 Ab+CLD treated mice as in a. d. UMAP plot of pancreas podoplanin⁺ fibroblasts from IgG+PBS or CSF1 Ab+CLD mice as in a. e. Heatmap displaying NES of gene sets significantly enriched across podoplanin⁺ fibroblast subtypes (as in c) comparing IgG+PBS to CSF1 Ab+CLD samples. f. Dot plot of DEGs upregulated in podoplanin⁺ fibroblasts from IgG+PBS or CSF1 Ab+CLD-treated mice as in a. g. Heatmaps displaying relative importance of network centrality measures for sender (ligand signals) and receiver (receptors) across macrophage clusters from Flt3-YFP mice treated with Cer by 6 hourly i.p. injections every other day for one week (from Fig. 3c) and fibroblast clusters as in a for PDGF, CCL, CSF1, VCAM and GAS signaling pathway networks from CellChat analysis⁴⁹. h. Violin plots showing expression of PDGF signaling pathway genes Pdgfa, Pdgfb, Pdgfc, Pdgfra and Pdgfrb across macrophage and fibroblast clusters as in g. i. Representative images of podoplanin or fibronectin-stained pancreas tissue from mice injected i.p with Veh or PDGFRi once per day along with 6 hourly Cer i.p. injections every other day for one week. Scale bars, 100μM. j. Quantification of podoplanin⁺ and fibronectin⁺ area in pancreas tissue of mice treated with Veh or PDGFRi and cerulein as in i; Veh, n=7 mice; PDGFRi, n=8 mice; *P=0.0205 in podoplanin analysis and *P=0.0140 in fibronectin analysis. k. Flow cytometry of podoplanin⁺ fibroblasts and density of PDGFRa⁺ fibroblasts from mice treated with Veh or PDGFRi along with Cer as in i,; n=7 mice/group and *P=0.0175. l. Body weight measurement and Kaplan-Meier survival curve in mice treated with Veh or PDGFRi along with 10μg/day Cer delivered by peritoneal osmotic pumps. Measurements start on day of osmotic pump implantation; n=10 mice/group, *P<0.0001 comparing vehicle and PDGFRi in survival curve. Data are presented as mean ± SEM unless otherwise indicated. n.s., not significant; *p <0.05. For comparisons between two groups, Student’s two-tailed t-test was used, except for f, where Bonferroni correction was used, and e, where FDR was used.