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Lang, N.J. ; Schniering, J. ; Porras-Gonzalez, D.L. ; Yang, L. ; De Sadeleer, L.J. ; Jentzsch, R.C. ; Shitov, V.A. ; Zhou, S. ; Ansari, M. ; Agami, A. ; Mayr, C. ; Hooshiar Kashani, B. ; Chen, Y. ; Heumos, L. ; Pestoni, J. ; Molnar, E.S. ; Geeraerts, E.* ; Anquetil, V.* ; Saniere, L.* ; Wögrath, M. ; Gerckens, M. ; Lehmann, M. ; Yildirim, A.Ö. ; Hatz, R.A.* ; Kneidinger, N. ; Behr, J. ; Wuyts, W.A.* ; Stoleriu, M.-G. ; Luecken, M. ; Theis, F.J. ; Burgstaller, G. ; Schiller, H.

Ex vivo tissue perturbations coupled to single-cell RNA-seq reveal multilineage cell circuit dynamics in human lung fibrogenesis.

Sci. Transl. Med. 15, 19:eadh0908 (2023)
Postprint DOI PMC
Open Access Green
Pulmonary fibrosis develops as a consequence of failed regeneration after injury. Analyzing mechanisms of regeneration and fibrogenesis directly in human tissue has been hampered by the lack of organotypic models and analytical techniques. In this work, we coupled ex vivo cytokine and drug perturbations of human precision-cut lung slices (hPCLS) with single-cell RNA sequencing and induced a multilineage circuit of fibrogenic cell states in hPCLS. We showed that these cell states were highly similar to the in vivo cell circuit in a multicohort lung cell atlas from patients with pulmonary fibrosis. Using micro-CT-staged patient tissues, we characterized the appearance and interaction of myofibroblasts, an ectopic endothelial cell state, and basaloid epithelial cells in the thickened alveolar septum of early-stage lung fibrosis. Induction of these states in the hPCLS model provided evidence that the basaloid cell state was derived from alveolar type 2 cells, whereas the ectopic endothelial cell state emerged from capillary cell plasticity. Cell-cell communication routes in patients were largely conserved in hPCLS, and antifibrotic drug treatments showed highly cell type-specific effects. Our work provides an experimental framework for perturbational single-cell genomics directly in human lung tissue that enables analysis of tissue homeostasis, regeneration, and pathology. We further demonstrate that hPCLS offer an avenue for scalable, high-resolution drug testing to accelerate antifibrotic drug development and translation.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Idiopathic Pulmonary-fibrosis; Pirfenidone; Deficiency; Nintedanib
Language english
Publication Year 2023
HGF-reported in Year 2023
ISSN (print) / ISBN 1946-6234
e-ISSN 1946-6242
Journal Science Translational Medicine
Quellenangaben Volume: 15, Issue: 725, Pages: 19, Article Number: eadh0908 Supplement: ,
Publisher American Association for the Advancement of Science (AAAS)
Publishing Place 1200 New York Ave, Nw, Washington, Dc 20005 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Lung Health and Immunity (LHI)
German Center for Lung Research (DZL)
Institute of Computational Biology (ICB)
POF-Topic(s) 30202 - Environmental Health
80000 - German Center for Lung Research
30205 - Bioengineering and Digital Health
Research field(s) Lung Research
Enabling and Novel Technologies
PSP Element(s) G-501693-001
G-501600-014
G-501800-810
G-505000-008
G-503800-001
G-501800-820
G-501600-001
G-501600-005
G-505000-007
G-501600-002
Grants Bundesinstitut fur Risikoforschung
Deutsche Forschungsgemeinschaft
German Center for Lung Research
Helmholtz Association
European Respiratory Society
Faculty of Medicine of the Ludwig-Maximilians-University Munich
Bavarian State Ministry of Science and Arts
Chan Zuckerberg Initiative
European Union
DOI 10.1126/scitranslmed.adh0908
WOS ID 001147917300001
PubMed ID 38055803
Erfassungsdatum 2023-12-20
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