PMID- 32109549
OWN - NLM
STAT- MEDLINE
DCOM- 20210809
LR  - 20220415
IS  - 1873-3913 (Electronic)
IS  - 0898-6568 (Print)
IS  - 0898-6568 (Linking)
VI  - 70
DP  - 2020 Jun
TI  - Chronic WNT/beta-catenin signaling induces cellular senescence in lung epithelial 
      cells.
PG  - 109588
LID - S0898-6568(20)30065-6 [pii]
LID - 10.1016/j.cellsig.2020.109588 [doi]
AB  - The rapid expansion of the elderly population has led to the recent epidemic of 
      age-related diseases, including increased incidence and mortality of chronic lung 
      diseases, such as Idiopathic Pulmonary Fibrosis (IPF). Cellular senescence is a 
      major hallmark of aging and has a higher occurrence in IPF. The lung epithelium 
      represents a major site of tissue injury, cellular senescence and aberrant 
      activity of developmental pathways such as the WNT/beta-catenin pathway in IPF. The 
      potential impact of WNT/beta-catenin signaling on alveolar epithelial senescence in 
      general as well as in IPF, however, remains elusive. Here, we characterized 
      alveolar epithelial cells of aged mice and assessed the contribution of chronic 
      WNT/beta-catenin signaling on alveolar epithelial type (AT) II cell senescence. 
      Whole lungs from old (16-24 months) versus young (3 months) mice had relatively 
      less epithelial (EpCAM(+)) but more inflammatory (CD45(+)) cells, as assessed by 
      flow cytometry. Compared to young ATII cells, old ATII cells showed decreased 
      expression of the ATII cell marker Surfactant Protein C along with increased 
      expression of the ATI cell marker Hopx, accompanied by increased WNT/beta-catenin 
      activity. Notably, when placed in an organoid assay, old ATII cells exhibited 
      decreased progenitor cell potential. Chronic canonical WNT/beta-catenin activation 
      for up to 7 days in primary ATII cells as well as alveolar epithelial cell lines 
      induced a robust cellular senescence, whereas the non-canonical ligand WNT5A was 
      not able to induce cellular senescence. Moreover, chronic WNT3A treatment of 
      precision-cut lung slices (PCLS) further confirmed ATII cell senescence. 
      Simultaneously, chronic but not acute WNT/beta-catenin activation induced a 
      profibrotic state with increased expression of the impaired ATII cell marker 
      Keratin 8. These results suggest that chronic WNT/beta-catenin activity in the IPF 
      lung contributes to increased ATII cell senescence and reprogramming. In the 
      fibrotic environment, WNT/beta-catenin signaling thus might lead to further 
      progenitor cell dysfunction and impaired lung repair.
CI  - Copyright (c) 2020. Published by Elsevier Inc.
FAU - Lehmann, Mareike
AU  - Lehmann M
AD  - Lung Repair and Regeneration Unit, Helmholtz-Zentrum Munich, 
      Ludwig-Maximilians-University, University Hospital Grosshadern, Member of the 
      German Center of Lung Research (DZL), Munich 81377, Germany; Division of 
      Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of 
      Colorado, Aurora, CO 80045, USA. Electronic address: 
      mareike.lehmann@helmholtz-muenchen.de.
FAU - Hu, Qianjiang
AU  - Hu Q
AD  - Lung Repair and Regeneration Unit, Helmholtz-Zentrum Munich, 
      Ludwig-Maximilians-University, University Hospital Grosshadern, Member of the 
      German Center of Lung Research (DZL), Munich 81377, Germany.
FAU - Hu, Yan
AU  - Hu Y
AD  - Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, 
      University of Colorado, Aurora, CO 80045, USA.
FAU - Hafner, Kathrin
AU  - Hafner K
AD  - Lung Repair and Regeneration Unit, Helmholtz-Zentrum Munich, 
      Ludwig-Maximilians-University, University Hospital Grosshadern, Member of the 
      German Center of Lung Research (DZL), Munich 81377, Germany.
FAU - Costa, Rita
AU  - Costa R
AD  - Lung Repair and Regeneration Unit, Helmholtz-Zentrum Munich, 
      Ludwig-Maximilians-University, University Hospital Grosshadern, Member of the 
      German Center of Lung Research (DZL), Munich 81377, Germany.
FAU - van den Berg, Anastasia
AU  - van den Berg A
AD  - Lung Repair and Regeneration Unit, Helmholtz-Zentrum Munich, 
      Ludwig-Maximilians-University, University Hospital Grosshadern, Member of the 
      German Center of Lung Research (DZL), Munich 81377, Germany.
FAU - Konigshoff, Melanie
AU  - Konigshoff M
AD  - Lung Repair and Regeneration Unit, Helmholtz-Zentrum Munich, 
      Ludwig-Maximilians-University, University Hospital Grosshadern, Member of the 
      German Center of Lung Research (DZL), Munich 81377, Germany; Division of 
      Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of 
      Colorado, Aurora, CO 80045, USA. Electronic address: 
      melanie.koenigshoff@cuanschutz.edu.
LA  - eng
GR  - F32 HL149290/HL/NHLBI NIH HHS/United States
GR  - R01 HL141380/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200226
PL  - England
TA  - Cell Signal
JT  - Cellular signalling
JID - 8904683
RN  - 0 (Wnt Proteins)
SB  - IM
MH  - *Alveolar Epithelial Cells/metabolism/pathology
MH  - Animals
MH  - Cell Line
MH  - *Cellular Senescence
MH  - Humans
MH  - Idiopathic Pulmonary Fibrosis/*metabolism
MH  - Lung/cytology/pathology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Wnt Proteins/*physiology
MH  - *Wnt Signaling Pathway
PMC - PMC8968687
MID - NIHMS1789093
OTO - NOTNLM
OT  - ATII cells
OT  - Aging
OT  - Cellular senescence
OT  - IPF
OT  - WNT signaling
EDAT- 2020/02/29 06:00
MHDA- 2021/08/10 06:00
PMCR- 2022/03/31
CRDT- 2020/02/29 06:00
PHST- 2019/10/26 00:00 [received]
PHST- 2020/02/21 00:00 [revised]
PHST- 2020/02/22 00:00 [accepted]
PHST- 2020/02/29 06:00 [pubmed]
PHST- 2021/08/10 06:00 [medline]
PHST- 2020/02/29 06:00 [entrez]
PHST- 2022/03/31 00:00 [pmc-release]
AID - S0898-6568(20)30065-6 [pii]
AID - 10.1016/j.cellsig.2020.109588 [doi]
PST - ppublish
SO  - Cell Signal. 2020 Jun;70:109588. doi: 10.1016/j.cellsig.2020.109588. Epub 2020 
      Feb 26.