Abstract
Fibroblasts are present throughout the body and function to maintain tissue homeostasis. Recent studies have identified diverse fibroblast subsets in healthy and injured tissues1,2, but the origins and functional roles of injury-induced fibroblast lineages remain unclear. Here we show that lung-specialized alveolar fibroblasts take on multiple molecular states with distinct roles in facilitating responses to fibrotic lung injury. We generate a genetic tool that uniquely targets alveolar fibroblasts to demonstrate their role in providing niches for alveolar stem cells in homeostasis and show that loss of this niche leads to exaggerated responses to acute lung injury. Lineage tracing identifies alveolar fibroblasts as the dominant origin for multiple emergent fibroblast subsets sequentially driven by inflammatory and pro-fibrotic signals after injury. We identify similar, but not completely identical, fibroblast lineages in human pulmonary fibrosis. TGFβ negatively regulates an inflammatory fibroblast subset that emerges early after injury and stimulates the differentiation into fibrotic fibroblasts to elicit intra-alveolar fibrosis. Blocking the induction of fibrotic fibroblasts in the alveolar fibroblast lineage abrogates fibrosis but exacerbates lung inflammation. These results demonstrate the multifaceted roles of the alveolar fibroblast lineage in maintaining normal alveolar homeostasis and orchestrating sequential responses to lung injury.
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Data availability
The scRNA-seq data generated in this study are deposited in Gene Expression Omnibus (GEO) under accession GSE210341. Human scRNA-seq data analyses were performed using publicly available data from accessions GSE132771, GSE147066 and GSE135893. Source data are provided with this paper.
Code availability
The codes used in the scRNA-seq analysis are available on GitHub (https://github.com/TatsuyaTsukui/AlveolarLineage).
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Acknowledgements
The authors thank J. Zhang for support with the generation of knock-in mice; W. Eckalbar for support with computational analysis; and C. Molina for assistance with experiments. T.T. was supported by the Japan Society for the Promotion of Science (JSPS Overseas Research Fellowship), the Uehara Memorial Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, and the Frontiers in Medical Research Fellowship from the California Foundation for Molecular Biology. This work was supported by HL155786 (T.T.), HL142568 (D.S.), a sponsored research agreement from AbbVie (D.S.), and the Nina Ireland Program for Lung Health (P.J.W.). We thank UCSF core facilities: Laboratory for Cell Analysis supported by P30CA082103, Center for Advanced Light Microscopy supported by S10 Shared Instrumentation grant (1S10OD017993-01A1), and UCSF PBBR, Gladstone Transgenic Gene Targeting Core, Gladstone Genomics core, and Center for Advanced Technology supported by UCSF PBBR, RRP IMIA, and 1S10OD028511-01.
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Contributions
T.T. and D.S. conceived the study, interpreted the data and wrote the manuscript. T.T. performed and analysed the experiments. P.J.W. procured human samples. D.S. supervised the study.
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Competing interests
D.S. is a founder of Pliant Therapeutics and has received research funding from Abbvie, Pfizer and Pliant Therapeutics. D.S. serves on the Scientific Review Board for Genentech and on the Inflammation Scientific Advisory Board for Amgen. P.J.W. received research funding from Boehringer Ingelheim, Pliant Therapeutics, and Genentech.
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Extended data figures and tables
Extended Data Fig. 1 Scube2-CreER specifically labels alveolar fibroblasts, which provide a niche to support AT2 cells.
a, UMAP plots of all lung cells from scRNA-seq data of ref. 2, for cell types (left) and Scube2 expression (right). b, UMAP plots of Col1a1+ cells from scRNA-seq data of ref. 2, for cell types (left) and Scube2 expression (right). c–f, Gating strategy to evaluate the specificity of tdTomato+ cells for lineage (CD31, CD45, EpCAM, Mcam, Ter119), Sca1, and CD9. g, Gating strategy for alveolar fibroblasts. h, Flow cytometric quantification for percent tdTomato+ of alveolar fibroblasts. n = 3 mice. i, Pi16 staining of a lung section from Scube2-CreER/Rosa26-tdTomato Col-GFP mouse. tdTomato is shown in magenta. Col-GFP is shown in green. Pi16 is shown in grey. DAPI is shown in blue. aw, airway. j, Three representative planes from z-stack images with z-positions are shown below the images. tdTomato is shown in red. proSP-C is shown in cyan. Asterisks indicate the same proSP-C+ cell. Arrows point to projections extending from alveolar fibroblasts. Scale bars, 200 μm (i) or 5 μm (j). Data are mean ± SEM. Data are representative of at least two independent experiments.
Extended Data Fig. 2 Scube2-CreER-labelled alveolar fibroblasts provide a niche to support AT2 cells.
a,b, Gating strategy for alveolar fibroblast-ablation experiments with Scube2-CreER/Rosa26-DTA mice. a, Gating strategy for EpCAM+ subpopulations. b, Gating strategy for fibroblast subsets. Lineage markers include CD31, CD45, EpCAM, and Ter119. c, Flow cytometric cell count for each population, normalized to means of vehicle groups. n = 4 (tamoxifen) or 5 (vehicle) mice. d, Representative images of H&E staining of lung sections from alveolar fibroblast-ablation experiments. Scale bars, 200 μm. e, Quantification of mean linear intercept of alveolar regions. n = 4 (tamoxifen) or 5 (vehicle) mice. f, qPCR analysis of whole lung cells 6 days after bleomycin treatment. n = 5 mice. g, Gating strategy for CD4 and γδ T cells. h, Gating strategy for ILCs. i, Flow cytometric quantification in bleomycin-treated lungs. n = 4 (Rosa26-DTA/DTA) or 7 (Rosa26-WT/WT) mice. j, Gating strategy for IL-17a+ cells. Data are mean ± SEM. Data are representative of at least two experiments. Statistical analysis was performed using unpaired two-tailed t-test followed by Holm–Sidak’s multiple-comparisons adjustment (f) or two-way ANOVA followed by Sidak’s multiple comparison test (i).
Extended Data Fig. 3 Longitudinal scRNA-seq reveals multiple fibroblast subsets that emerge after lung injury.
a, Gating strategy for purifying lineage (CD31, CD45, EpCAM, Ter119)− mesenchymal cells for scRNA-seq. b, UMAP plots for cells obtained before (day 0) or at various time points after bleomycin treatment. c, Dot plots showing the top differentially expressed genes for each cluster. d, GO enrichment analysis by DAVID for differentially expressed genes of inflammatory fibroblasts. e, GO enrichment analysis by DAVID for differentially expressed genes of stress-activated fibroblasts. f, GO over-representation analysis with the Fisher test for all clusters.
Extended Data Fig. 4 Lineage tracing by scRNA-seq reveals alveolar fibroblasts as the origin of multiple pathologic fibroblast subsets.
a, UMAP plot with tdTomato expression. b, Violin plot for tdTomato shows peaks for tdTomatolow or tdTomatohigh cells. The threshold for tdTomato+ cells was defined as an expression level > 3.5. c, UMAP plots with tdTomato expression split by biological replicates. d, Plot showing percent tdTomato+ of alveolar fibroblasts (x-axis) versus percent tdTomato+ of fibrotic fibroblasts (y-axis) for each biological replicate.
Extended Data Fig. 5 Scube2-CreER-labelled alveolar fibroblasts differentiate into fibrotic or inflammatory fibroblasts after lung injury.
a, Maximum projection of whole lung imaging for untreated or bleomycin day 14 Scube2-CreER/Rosa26-tdTomato mice. b, Representative optical sections from whole lung imaging. tdTomato is shown in magenta. Autofluorescence is shown in grey (a, b). c, Flow cytometry plots showing the increase of CD9+ cells among Scube2-CreER-labeled (tdTomato+) cells on day 21 after bleomycin treatment. d, Flow cytometric quantification of percent CD9+ of tdTomato+ cells. n = 4 mice. Statistical analysis was performed using unpaired two-tailed t-test. e, qPCR analysis of sorted cells from Scube2-CreER/Rosa26-tdTomato mice. All lineage (CD31, CD45, EpCAM, Ter119)− tdTomato+ cells (untreated or bleomycin day 21) or lineage− tdTomato+ CD9+ cells (bleomycin day 21) were sorted. The y-axis is the relative expression level to the housekeeping gene Rps3. n = 3 mice. f, Saa3 staining in sections from Scube2-CreER/Rosa26-tdTomato mice 7 days after bleomycin treatment. Arrows indicate tdTomato and Saa3 double-positive cells. g, Quantification of percent Saa3+ of tdTomato+ cells. n = 3 mice. tdTomato is shown in red. Saa3 is shown in cyan. DAPI is shown in blue. Collagen 4 is shown in grey. Data are mean ± SEM. Data are representative of at least two independent experiments. Scale bars, 1 mm (a, b), 20 μm (f).
Extended Data Fig. 6 Alveolar fibroblasts up-regulated activation markers and formed silicotic nodules in the silicosis model.
a, Time course of tamoxifen and silica treatment. b, Representative lung sections of saline or silica-treated mice. c,d, Sirius red staining of silica-treated lung section imaged as bright field (c) or polarized light (d). e, Fluorescence imaging of a sequential section of c,d. f, Representative images of silicotic nodules. g, Histological quantification of % tdTomato+ cells of Pdgfra+ cells inside silicotic nodules. n = 5 mice. h, Flow cytometric analysis of Pdgfra and CD9 on tdTomato+ cells from saline or silica-treated lungs. i, Flow cytometric quantification of %CD9+ Pdgfra-low cells of tdTomato+ cells. n = 5 mice. j,k, qPCR analysis of purified populations. The y-axis is the relative expression level to the housekeeping gene Rps3. n = 5 mice. Scale bars, 200 μm (b), 500 μm (c-e), 50 μm (f). Data are mean ± SEM. Data are representative of at least two independent experiments. Statistical analysis was performed using unpaired two-tailed t-test (i,k) or Tukey’s multiple comparisons test after one-way ANOVA (j).
Extended Data Fig. 7 TGF-β1 antagonizes inflammatory marker expression induced by IL-1β and induces fibrotic markers.
a, Pseudotime analysis of tdTomato+ clusters suggests that both stress-activated fibroblasts and fibrotic fibroblasts can emerge from inflammatory fibroblasts. b, UMAP plots of re-clustered alveolar, inflammatory, and fibrotic lineage split by days after bleomycin treatment. c, Expression of selected markers on UMAP plots. d, Schematic of sequential cytokine stimulations for primary alveolar fibroblasts. e, qPCR analysis after sequential cytokine stimulations. Group names indicate (first stimulation) → (second stimulation). DMEM means medium-only control. The y-axis is the relative expression level to the housekeeping gene Rps3. n = 3 wells. Data are mean ± SEM. Data are representative of two independent experiments.
Extended Data Fig. 8 Re-analysis of our publicly available scRNA-seq data from human pulmonary fibrosis reveals inflammatory and fibrotic clusters.
a, UMAP plots of re-clustered pathologic and alveolar clusters shown for individual patients or donors (control). b, Dot plot showing top differentially expressed genes for each cluster. c, GO enrichment analysis by DAVID for differentially expressed genes in inflammatory fibroblast 1 cluster. d, GO enrichment analysis by DAVID for differentially expressed genes in inflammatory fibroblast 2 cluster. e, Heat map showing Spearman’s correlation coefficients of average gene expression from mouse and human emergent clusters. f, GO over-representation analysis with the Fisher test for all clusters.
Extended Data Fig. 9 Combined analysis of publicly available scRNA-seq data sets from human pulmonary fibrosis from 3 groups reveals conserved inflammatory and fibrotic clusters.
a, UMAP plot of mesenchymal cells from ref. 23. b, Expression levels of selected genes on UMAP plot of mesenchymal cells in ref. 23 show alveolar and pathologic fibroblast clusters. c, UMAP plot of mesenchymal cells from ref. 24. d, Expression levels of selected genes on UMAP plot of mesenchymal cells from ref. 24 show that the “Myofibroblasts” cluster contains alveolar and pathologic fibroblasts. e, UMAP plot after combining alveolar and pathologic fibroblasts from refs. 2,23,24. f, UMAP plots of combined data split by original data set. g, UMAP plots shown for each data set and coloured by samples. h, Expression levels of selected markers for fibrotic (COL1A1, CTHRC1), inflammatory1 (SFRP2, CXCL12), inflammatory2 (SFRP4, CXCL14) and alveolar fibroblasts (NPNT, TCF21) on UMAP plots.
Extended Data Fig. 10 Cthrc1-CreER mouse demonstrates the pro-fibrotic function of Cthrc1+ fibroblasts.
a, Gating strategy for cell size, singlet, and live cells. b, Flow cytometry plots show an increase in lineage− tdTomato+ cells on day 14 after bleomycin treatment. c, Flow cytometric cell count of lineage (CD31, CD45, EpCAM, Ter119)− tdTomato+ cells on day 14. n = 3 (Saline-Vehicle) or 5 (Saline-Tamoxifen, Bleo-Tamoxifen) mice. d, Flow cytometry plots show CD9 expression on tdTomato+ lineage− cells increases between day 14 and 21. e, Flow cytometric quantification of percent CD9+ of tdTomato+ lineage− cells. n = 5 mice. f, Mean fluorescence intensity (MFI) of CD9 on tdTomato+ lineage− cells. n = 5 mice. g, Saa3 staining in sections from Cthrc1-CreER/Rosa26-tdTomato mice 14 days after bleomycin treatment with tamoxifen injected on days 8 -12. tdTomato is shown in red. Saa3 is shown in cyan. Collagen 4 is shown in grey. DAPI is shown in blue. h, Schematic for localization of inflammatory and fibrotic fibroblasts. i, Representative images of sequential lung sections from Cthrc1-CreER/Rosa26-tdTomato mice stained for collagen 1 or Pi16 (shown in grey). tdTomato is shown in red. DAPI is shown in blue. j,k, Image quantifications of the mean distance to collagen 1 or Pi16 from tdTomato or DAPI on the sections. n = 4 mice. l, Representative images of lung sections stained for collagen 1 (shown in grey) from ablation experiments using Cthrc1-CreER/Rosa26-DTA mice. DAPI is shown in blue. m, Image quantification of % collagen 1+ area on the sections. n = 3 (saline), 8 (bleomycin, Rosa26-WT/WT), or 10 (bleomycin, Rosa26-DTA/DTA) mice. Data are mean ± SEM. Data are representative of at least two independent experiments. Scale bars, 20 μm (g), 1 mm (i,l). Statistical analysis was performed using unpaired two-tailed t-test (j,k) or two-way ANOVA followed by Sidak’s multiple comparison test (m).
Extended Data Fig. 11 Tgfbr2 conditional knockout in alveolar fibroblasts abrogates fibrosis but exacerbates inflammation.
a, Representative images of whole sections stained for collagen 1 (magenta) and collagen 4 (green). Arrows indicate regions of intra-alveolar collagen 1. b, Survival after bleomycin treatment. n = 15 mice. c, qPCR of purified tdTomato+ cells from saline-treated mice showed no difference for fibrotic and inflammatory genes between control and Tgfbr2 cKO. d, Flow cytometric counting of myeloid populations in BAL from saline-treated mice showed no difference between control and Tgfbr2 cKO. n = 5 mice (b,c). e, Gating strategy for myeloid populations in BAL. f, Representative images of sections from bleomycin-treated lungs stained for Saa3 (magenta) and CD68 (green). tdTomato is shown in blue. Magnified single-channel images of yellow rectangles are shown on the right. g,h, Image quantification of Saa3 (g), or CD68 (h). n = 5 (control) or 6 (Tgfbr2 fl/fl) mice. Data are representative of at least two independent experiments. Data are mean ± SEM. Statistical analysis was performed using unpaired two-tailed t-test (g,h). Scale bars, 1 mm (a), 100 μm (f, wide), or 20 μm (f, magnified).
Supplementary information
Supplementary Table 1
Primer sequences used for qPCR.
Supplementary Video 1
3D reconstruction of z-stack images for a section from an uninjured Scube2-creER mouse. z-stack images of a thick section from an uninjured Scube2-creER mouse lung stained for proSP-C and nuclei were reconstructed in 3D. tdTomato is shown in red. proSP-C is shown in cyan. DAPI (nuclei) is shown in blue.
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Tsukui, T., Wolters, P.J. & Sheppard, D. Alveolar fibroblast lineage orchestrates lung inflammation and fibrosis. Nature 631, 627–634 (2024). https://doi.org/10.1038/s41586-024-07660-1
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DOI: https://doi.org/10.1038/s41586-024-07660-1
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