| Autor: |
Braeuer RR; Department of Internal Medicine., Walker NM; Department of Internal Medicine., Misumi K; Department of Internal Medicine., Mazzoni-Putman S; Department of Internal Medicine., Aoki Y; Department of Internal Medicine., Liao R; Department of Computational Medicine and Bioinformatics., Vittal R; Department of Internal Medicine., Kleer GG; Department of Internal Medicine., Wheeler DS; Department of Internal Medicine., Sexton JZ; Department of Pharmacy., Farver CF; Department of Pathology, and., Welch JD; Department of Computational Medicine and Bioinformatics.; Department of Computer Science and Engineering, University of Michigan, Ann Arbor, Michigan, USA., Lama VN; Department of Internal Medicine. |
| Jazyk: |
angličtina |
| Zdroj: |
The Journal of clinical investigation [J Clin Invest] 2021 Nov 01; Vol. 131 (21). |
| DOI: |
10.1172/JCI147343 |
| Abstrakt: |
In this study, we demonstrate that forkhead box F1 (FOXF1), a mesenchymal transcriptional factor essential for lung development, was retained in a topographically distinct mesenchymal stromal cell population along the bronchovascular space in an adult lung and identify this distinct subset of collagen-expressing cells as key players in lung allograft remodeling and fibrosis. Using Foxf1-tdTomato BAC (Foxf1-tdTomato) and Foxf1-tdTomato Col1a1-GFP mice, we show that Lin-Foxf1+ cells encompassed the stem cell antigen 1+CD34+ (Sca1+CD34+) subset of collagen 1-expressing mesenchymal cells (MCs) with a capacity to generate CFU and lung epithelial organoids. Histologically, FOXF1-expressing MCs formed a 3D network along the conducting airways; FOXF1 was noted to be conspicuously absent in MCs in the alveolar compartment. Bulk and single-cell RNA-Seq confirmed distinct transcriptional signatures of Foxf1+ and Foxf1- MCs, with Foxf1-expressing cells delineated by their high expression of the transcription factor glioma-associated oncogene 1 (Gli1) and low expression of integrin α8 (Itga), versus other collagen-expressing MCs. FOXF1+Gli1+ MCs showed proximity to Sonic hedgehog-expressing (Shh-expressing) bronchial epithelium, and mesenchymal expression of Foxf1 and Gli1 was found to be dependent on paracrine Shh signaling in epithelial organoids. Using a murine lung transplant model, we show dysregulation of epithelial-mesenchymal SHH/GLI1/FOXF1 crosstalk and expansion of this specific peribronchial MC population in chronically rejecting fibrotic lung allografts. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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