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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)
DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Idiopathic Pulmonary-fibrosis; Pirfenidone; Deficiency; Nintedanib
ISSN (print) / ISBN 1946-6234
e-ISSN 1946-6242
Zeitschrift Science Translational Medicine
Quellenangaben Band: 15, Heft: 725, Seiten: 19, Artikelnummer: eadh0908 Supplement: ,
Verlag American Association for the Advancement of Science (AAAS)
Verlagsort 1200 New York Ave, Nw, Washington, Dc 20005 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Lung Health and Immunity (LHI)
Institute of Computational Biology (ICB)
Institute of Lung Biology (LHI)
Förderungen 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