Lung Injury Induces Alveolar Type 2 Cell Hypertrophy and Polyploidy with Implications for Repair and Regeneration

Anthea Weng; Mariana Maciel Herrerias; Satoshi Watanabe; Lynn C. Welch; Annette S. Flozak; Rogan A. Grant; Raul Piseaux Aillon; Laura A. Dada; SeungHye Han; Monique E Hinchcliff; Alexander V. Misharin; G. R.Scott Budinger; Cara J. Gottardi

doi:10.1165/rcmb.2021-0356OC

Lung Injury Induces Alveolar Type 2 Cell Hypertrophy and Polyploidy with Implications for Repair and Regeneration

Anthea Weng, Mariana Maciel Herrerias, Satoshi Watanabe, Lynn C. Welch, Annette S. Flozak, Rogan A. Grant, Raul Piseaux Aillon, Laura A. Dada, SeungHye Han, Monique E Hinchcliff, Alexander V. Misharin, G. R.Scott Budinger, Cara J. Gottardi

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	564-576
Number of pages	13
Journal	American journal of respiratory cell and molecular biology
Volume	66
Issue number	5
DOIs	https://doi.org/10.1165/rcmb.2021-0356OC
State	Published - May 2022

Funding

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.). 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\u2019s Atomic and Nanoscale Characterization Experimental Center (National Science Foundation grants ECCS-2025633, DMR-1720139).

Keywords

alveolar epithelial cell
cytokinesis
hypertrophy
integrated stress response
polyploidy

ASJC Scopus subject areas

Molecular Biology
Pulmonary and Respiratory Medicine
Clinical Biochemistry
Cell Biology

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Weng, A., Maciel Herrerias, M., Watanabe, S., Welch, L. C., Flozak, A. S., Grant, R. A., Aillon, R. P., Dada, L. A., Han, S., Hinchcliff, M. E., Misharin, A. V., Budinger, G. R. S., & Gottardi, C. J. (2022). Lung Injury Induces Alveolar Type 2 Cell Hypertrophy and Polyploidy with Implications for Repair and Regeneration. American journal of respiratory cell and molecular biology, 66(5), 564-576. https://doi.org/10.1165/rcmb.2021-0356OC

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title = "Lung Injury Induces Alveolar Type 2 Cell Hypertrophy and Polyploidy with Implications for Repair and Regeneration",

abstract = "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.",

keywords = "alveolar epithelial cell, cytokinesis, hypertrophy, integrated stress response, polyploidy",

author = "Anthea Weng and {Maciel Herrerias}, Mariana and Satoshi Watanabe and Welch, {Lynn C.} and Flozak, {Annette S.} and Grant, {Rogan A.} and Aillon, {Raul Piseaux} and Dada, {Laura A.} and SeungHye Han and Hinchcliff, {Monique E} and Misharin, {Alexander V.} and Budinger, {G. R.Scott} and Gottardi, {Cara J.}",

year = "2022",

month = may,

doi = "10.1165/rcmb.2021-0356OC",

language = "English (US)",

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Weng, A, Maciel Herrerias, M, Watanabe, S, Welch, LC, Flozak, AS, Grant, RA, Aillon, RP, Dada, LA , Han, S, Hinchcliff, ME, Misharin, AV , Budinger, GRS & Gottardi, CJ 2022, 'Lung Injury Induces Alveolar Type 2 Cell Hypertrophy and Polyploidy with Implications for Repair and Regeneration', American journal of respiratory cell and molecular biology, vol. 66, no. 5, pp. 564-576. https://doi.org/10.1165/rcmb.2021-0356OC

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.

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

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Lung Injury Induces Alveolar Type 2 Cell Hypertrophy and Polyploidy with Implications for Repair and Regeneration

Abstract

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