PMID- 37577522
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231019
DP  - 2023 Aug 4
TI  - A fibroblast-dependent TGFbeta1/sFRP2 noncanonical Wnt signaling axis underlies 
      epithelial metaplasia in idiopathic pulmonary fibrosis.
LID - 2023.08.02.551383 [pii]
LID - 10.1101/2023.08.02.551383 [doi]
AB  - Reciprocal interactions between alveolar fibroblasts and epithelial cells are 
      crucial for lung homeostasis, injury repair, and fibrogenesis, but underlying 
      mechanisms remain unclear. To investigate this, we administered the 
      fibroblast-selective TGFbeta1 signaling inhibitor, epigallocatechin gallate (EGCG), 
      to Interstitial Lung Disease (ILD) patients undergoing diagnostic lung biopsy and 
      conducted single-cell RNA sequencing on spare tissue. Unexposed biopsy samples 
      showed higher fibroblast TGFbeta1 signaling compared to non-disease donor or 
      end-stage ILD tissues. In vivo, EGCG significantly downregulated TGFbeta1 signaling 
      and several pro-inflammatory and stress pathways in biopsy samples. Notably, EGCG 
      reduced fibroblast secreted Frizzle-like Receptor Protein 2 (sFRP2), an 
      unrecognized TGFbeta1 fibroblast target gene induced near type II alveolar 
      epithelial cells (AEC2s). In human AEC2-fibroblast coculture organoids, sFRP2 was 
      essential for AEC2 trans-differentiation to basal cells. Precision cut lung 
      slices (PCLS) from normal donors demonstrated that TGFbeta1 promoted KRT17 
      expression and AEC2 morphological change, while sFRP2 was necessary for KRT5 
      expression in AEC2-derived basaloid cells. Wnt-receptor Frizzled 5 (Fzd5) 
      expression and downstream calcineurin-related signaling in AEC2s were required 
      for sFRP2-induced KRT5 expression. These findings highlight stage-specific TGFbeta1 
      signaling in ILD, the therapeutic potential of EGCG in reducing IPF-related 
      transcriptional changes, and identify the TGFbeta1-non-canonical Wnt pathway 
      crosstalk via sFRP2 as a novel mechanism for dysfunctional epithelial signaling 
      in Idiopathic Pulmonary Fibrosis/ILD.
FAU - Cohen, Max L
AU  - Cohen ML
AD  - Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep 
      Medicine; University of California San Francisco, San Francisco, California.
FAU - Brumwell, Alexis N
AU  - Brumwell AN
AD  - Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep 
      Medicine; University of California San Francisco, San Francisco, California.
FAU - Che Ho, Tsung
AU  - Che Ho T
AD  - Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep 
      Medicine; University of California San Francisco, San Francisco, California.
FAU - Montas, Genevieve
AU  - Montas G
AD  - Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep 
      Medicine; University of California San Francisco, San Francisco, California.
FAU - Golden, Jeffrey A
AU  - Golden JA
AD  - Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep 
      Medicine; University of California San Francisco, San Francisco, California.
FAU - Jones, Kirk D
AU  - Jones KD
AD  - Department of Pathology; University of California San Francisco, San Francisco, 
      California.
FAU - Wolters, Paul J
AU  - Wolters PJ
AD  - Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep 
      Medicine; University of California San Francisco, San Francisco, California.
FAU - Wei, Ying
AU  - Wei Y
AD  - Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep 
      Medicine; University of California San Francisco, San Francisco, California.
FAU - Chapman, Harold A
AU  - Chapman HA
AD  - Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep 
      Medicine; University of California San Francisco, San Francisco, California.
FAU - Le Saux, Claude J
AU  - Le Saux CJ
AD  - Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep 
      Medicine; University of California San Francisco, San Francisco, California.
LA  - eng
GR  - F32 HL156356/HL/NHLBI NIH HHS/United States
GR  - R35 HL150767/HL/NHLBI NIH HHS/United States
GR  - T32 HL007185/HL/NHLBI NIH HHS/United States
GR  - U01 HL134766/HL/NHLBI NIH HHS/United States
PT  - Preprint
DEP - 20230804
PL  - United States
TA  - bioRxiv
JT  - bioRxiv : the preprint server for biology
JID - 101680187
PMC - PMC10418166
EDAT- 2023/08/14 06:41
MHDA- 2023/08/14 06:42
PMCR- 2023/08/11
CRDT- 2023/08/14 05:01
PHST- 2023/08/14 06:41 [pubmed]
PHST- 2023/08/14 06:42 [medline]
PHST- 2023/08/14 05:01 [entrez]
PHST- 2023/08/11 00:00 [pmc-release]
AID - 2023.08.02.551383 [pii]
AID - 10.1101/2023.08.02.551383 [doi]
PST - epublish
SO  - bioRxiv [Preprint]. 2023 Aug 4:2023.08.02.551383. doi: 10.1101/2023.08.02.551383.