TY - JOUR
T1 - Lung Injury Induces Alveolar Type 2 Cell Hypertrophy and Polyploidy with Implications for Repair and Regeneration
AU - Weng, Anthea
AU - Maciel Herrerias, Mariana
AU - Watanabe, Satoshi
AU - Welch, Lynn C.
AU - Flozak, Annette S.
AU - Grant, Rogan A.
AU - Aillon, Raul Piseaux
AU - Dada, Laura A.
AU - Han, SeungHye
AU - Hinchcliff, Monique E
AU - Misharin, Alexander V.
AU - Budinger, G. R.Scott
AU - Gottardi, Cara J.
N1 - Funding Information:
Acknowledgment: This work relied on the following Northwestern University services and core facilities: Flow Cytometry (National Cancer Institute grants CA060553, 1S10OD011996, 1S10OD026814); Center for Advanced Microscopy (National Cancer Institute cancer center support grant P30 CA060553; National Center for Research Resources grants 1S10 RR031680, 1S10OD021704); BioCryo facility of Northwestern University’s Atomic and Nanoscale Characterization Experimental Center (National Science Foundation grants ECCS-2025633, DMR-1720139).
Funding Information:
Supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases grant AR073270 (M.H.); National Heart, Lung, and Blood Institute (NHLBI) grants HL135124 and HL153312, National Institute on Aging grant AG049665, and National Institute of Allergy and Infectious Diseases grant AI135964 (A.V.M.); National Institute of Environmental Health Sciences grant ES13995, NHLBI grant HL071643, and National Institute on Aging grant AG049665 (G.R.S.B.); and NHLBI grant HL134800, National Institute of Arthritis and Musculoskeletal and Skin Diseases grant AR073270, and National Institute of General Medical Sciences grant GM129312 (C.J.G.).
Publisher Copyright:
© 2022 American Thoracic Society. All rights reserved.
PY - 2022/5
Y1 - 2022/5
N2 - Epithelial polyploidization after injury is a conserved phenomenon recently shown to improve barrier restoration during wound healing. Whether lung injury can induce alveolar epithelial polyploidy is not known. We show that bleomycin injury induces alveolar type 2 cell (AT2) hypertrophy and polyploidy. AT2 polyploidization is also seen in short term ex vivo cultures, where AT2-to-AT1 transdifferentiation is associated with substantial binucleation due to failed cytokinesis. Both hypertrophic and polyploid features of AT2 cells can be attenuated by inhibiting the integrated stress response using the small molecule ISRIB. These data suggest that AT2 hypertrophic growth and polyploidization may be a feature of alveolar epithelial injury. Because AT2 cells serve as facultative progenitors for the distal lung epithelium, a propensity for injury-induced binucleation has implications for AT2 selfrenewal and regenerative potential upon reinjury, which may benefit from targeting the integrated stress response.
AB - Epithelial polyploidization after injury is a conserved phenomenon recently shown to improve barrier restoration during wound healing. Whether lung injury can induce alveolar epithelial polyploidy is not known. We show that bleomycin injury induces alveolar type 2 cell (AT2) hypertrophy and polyploidy. AT2 polyploidization is also seen in short term ex vivo cultures, where AT2-to-AT1 transdifferentiation is associated with substantial binucleation due to failed cytokinesis. Both hypertrophic and polyploid features of AT2 cells can be attenuated by inhibiting the integrated stress response using the small molecule ISRIB. These data suggest that AT2 hypertrophic growth and polyploidization may be a feature of alveolar epithelial injury. Because AT2 cells serve as facultative progenitors for the distal lung epithelium, a propensity for injury-induced binucleation has implications for AT2 selfrenewal and regenerative potential upon reinjury, which may benefit from targeting the integrated stress response.
KW - alveolar epithelial cell
KW - cytokinesis
KW - hypertrophy
KW - integrated stress response
KW - polyploidy
UR - http://www.scopus.com/inward/record.url?scp=85129681165&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85129681165&partnerID=8YFLogxK
U2 - 10.1165/rcmb.2021-0356OC
DO - 10.1165/rcmb.2021-0356OC
M3 - Article
C2 - 35202558
AN - SCOPUS:85129681165
VL - 66
SP - 564
EP - 576
JO - American Journal of Respiratory Cell and Molecular Biology
JF - American Journal of Respiratory Cell and Molecular Biology
SN - 1044-1549
IS - 5
ER -