Hypercapnia alters stromal-derived Wnt production limiting β-catenin signaling and proliferation in alveolar type 2 cells

Autores
Dada, Laura Andrea; Welch, Lynn C.; Magnani, Natalia Daniela; Ren, Ziyou; Han, Hyebin; Brazee, Patricia L.; Celli, Diego; Flozak, Annette S.; Weng, Anthea; Herrerias, Mariana Maciel; Kryvenko, Vitalii; Vadász, István; Runyan, Constance E.; Abdala Valencia, Hiam; Shigemura, Masahiko; Casalino Matsuda, S. Marina; Misharin, Alexander V.; Budinger, G. R. Scott; Gottardi, Cara J.; Sznajder, Jacob I.
Año de publicación
2023
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Persistent symptoms and radiographic abnormalities suggestive of failed lung repair are among the most common symptoms in patients with COVID-19 after hospital discharge. In mechanically ventilated patients with acute respiratory distress syndrome (ARDS) secondary to SARS-CoV-2 pneumonia, low tidal volumes to reduce ventilator-induced lung injury necessarily elevate blood CO2 levels, often leading to hypercapnia. The role of hypercapnia on lung repair after injury is not completely understood. Here - using a mouse model of hypercapnia exposure, cell lineage tracing, spatial transcriptomics, and 3D cultures - we show that hypercapnia limits β-catenin signaling in alveolar type II (AT2) cells, leading to their reduced proliferative capacity. Hypercapnia alters expression of major Wnts in PDGFRα+ fibroblasts from those maintaining AT2 progenitor activity toward those that antagonize β-catenin signaling, thereby limiting progenitor function. Constitutive activation of β-catenin signaling in AT2 cells or treatment of organoid cultures with recombinant WNT3A protein bypasses the inhibitory effects of hypercapnia. Inhibition of AT2 proliferation in patients with hypercapnia may contribute to impaired lung repair after injury, preventing sealing of the epithelial barrier and increasing lung flooding, ventilator dependency, and mortality.
Fil: Dada, Laura Andrea. Northwestern University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Welch, Lynn C.. Northwestern University; Estados Unidos
Fil: Magnani, Natalia Daniela. Northwestern University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Ren, Ziyou. Northwestern University; Estados Unidos
Fil: Han, Hyebin. Northwestern University; Estados Unidos
Fil: Brazee, Patricia L.. Northwestern University; Estados Unidos
Fil: Celli, Diego. Northwestern University; Estados Unidos
Fil: Flozak, Annette S.. Northwestern University; Estados Unidos
Fil: Weng, Anthea. Northwestern University; Estados Unidos
Fil: Herrerias, Mariana Maciel. Northwestern University; Estados Unidos
Fil: Kryvenko, Vitalii. Justus Liebig Universitat Giessen.; Alemania
Fil: Vadász, István. Justus Liebig Universitat Giessen.; Alemania
Fil: Runyan, Constance E.. Northwestern University; Estados Unidos
Fil: Abdala Valencia, Hiam. Northwestern University; Estados Unidos
Fil: Shigemura, Masahiko. Northwestern University; Estados Unidos
Fil: Casalino Matsuda, S. Marina. Northwestern University; Estados Unidos
Fil: Misharin, Alexander V.. Northwestern University; Estados Unidos
Fil: Budinger, G. R. Scott. Northwestern University; Estados Unidos
Fil: Gottardi, Cara J.. Northwestern University; Estados Unidos
Fil: Sznajder, Jacob I.. Northwestern University; Estados Unidos
Materia
HYPERCAPNIA
ALVEOLAR CELLS
PROLIFERATION
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/228061
Acceder
id CONICETDig_1accec1f4a49bdc9a19fc86cf101476a
oai_identifier_str oai:ri.conicet.gov.ar:11336/228061
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Hypercapnia alters stromal-derived Wnt production limiting β-catenin signaling and proliferation in alveolar type 2 cellsDada, Laura AndreaWelch, Lynn C.Magnani, Natalia DanielaRen, ZiyouHan, HyebinBrazee, Patricia L.Celli, DiegoFlozak, Annette S.Weng, AntheaHerrerias, Mariana MacielKryvenko, VitaliiVadász, IstvánRunyan, Constance E.Abdala Valencia, HiamShigemura, MasahikoCasalino Matsuda, S. MarinaMisharin, Alexander V.Budinger, G. R. ScottGottardi, Cara J.Sznajder, Jacob I.HYPERCAPNIAALVEOLAR CELLSPROLIFERATIONhttps://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3Persistent symptoms and radiographic abnormalities suggestive of failed lung repair are among the most common symptoms in patients with COVID-19 after hospital discharge. In mechanically ventilated patients with acute respiratory distress syndrome (ARDS) secondary to SARS-CoV-2 pneumonia, low tidal volumes to reduce ventilator-induced lung injury necessarily elevate blood CO2 levels, often leading to hypercapnia. The role of hypercapnia on lung repair after injury is not completely understood. Here - using a mouse model of hypercapnia exposure, cell lineage tracing, spatial transcriptomics, and 3D cultures - we show that hypercapnia limits β-catenin signaling in alveolar type II (AT2) cells, leading to their reduced proliferative capacity. Hypercapnia alters expression of major Wnts in PDGFRα+ fibroblasts from those maintaining AT2 progenitor activity toward those that antagonize β-catenin signaling, thereby limiting progenitor function. Constitutive activation of β-catenin signaling in AT2 cells or treatment of organoid cultures with recombinant WNT3A protein bypasses the inhibitory effects of hypercapnia. Inhibition of AT2 proliferation in patients with hypercapnia may contribute to impaired lung repair after injury, preventing sealing of the epithelial barrier and increasing lung flooding, ventilator dependency, and mortality.Fil: Dada, Laura Andrea. Northwestern University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Welch, Lynn C.. Northwestern University; Estados UnidosFil: Magnani, Natalia Daniela. Northwestern University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ren, Ziyou. Northwestern University; Estados UnidosFil: Han, Hyebin. Northwestern University; Estados UnidosFil: Brazee, Patricia L.. Northwestern University; Estados UnidosFil: Celli, Diego. Northwestern University; Estados UnidosFil: Flozak, Annette S.. Northwestern University; Estados UnidosFil: Weng, Anthea. Northwestern University; Estados UnidosFil: Herrerias, Mariana Maciel. Northwestern University; Estados UnidosFil: Kryvenko, Vitalii. Justus Liebig Universitat Giessen.; AlemaniaFil: Vadász, István. Justus Liebig Universitat Giessen.; AlemaniaFil: Runyan, Constance E.. Northwestern University; Estados UnidosFil: Abdala Valencia, Hiam. Northwestern University; Estados UnidosFil: Shigemura, Masahiko. Northwestern University; Estados UnidosFil: Casalino Matsuda, S. Marina. Northwestern University; Estados UnidosFil: Misharin, Alexander V.. Northwestern University; Estados UnidosFil: Budinger, G. R. Scott. Northwestern University; Estados UnidosFil: Gottardi, Cara J.. Northwestern University; Estados UnidosFil: Sznajder, Jacob I.. Northwestern University; Estados UnidosAmerican Society for Clinical Investigation2023-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/228061Dada, Laura Andrea; Welch, Lynn C.; Magnani, Natalia Daniela; Ren, Ziyou; Han, Hyebin; et al.; Hypercapnia alters stromal-derived Wnt production limiting β-catenin signaling and proliferation in alveolar type 2 cells; American Society for Clinical Investigation; JCI Insight; 8; 4; 1-2023; 1-382379-3708CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://insight.jci.org/articles/view/159331info:eu-repo/semantics/altIdentifier/doi/10.1172/jci.insight.159331info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:46:20Zoai:ri.conicet.gov.ar:11336/228061instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:46:21.21CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Hypercapnia alters stromal-derived Wnt production limiting β-catenin signaling and proliferation in alveolar type 2 cells
title Hypercapnia alters stromal-derived Wnt production limiting β-catenin signaling and proliferation in alveolar type 2 cells
spellingShingle Hypercapnia alters stromal-derived Wnt production limiting β-catenin signaling and proliferation in alveolar type 2 cells
Dada, Laura Andrea
HYPERCAPNIA
ALVEOLAR CELLS
PROLIFERATION
title_short Hypercapnia alters stromal-derived Wnt production limiting β-catenin signaling and proliferation in alveolar type 2 cells
title_full Hypercapnia alters stromal-derived Wnt production limiting β-catenin signaling and proliferation in alveolar type 2 cells
title_fullStr Hypercapnia alters stromal-derived Wnt production limiting β-catenin signaling and proliferation in alveolar type 2 cells
title_full_unstemmed Hypercapnia alters stromal-derived Wnt production limiting β-catenin signaling and proliferation in alveolar type 2 cells
title_sort Hypercapnia alters stromal-derived Wnt production limiting β-catenin signaling and proliferation in alveolar type 2 cells
dc.creator.none.fl_str_mv Dada, Laura Andrea
Welch, Lynn C.
Magnani, Natalia Daniela
Ren, Ziyou
Han, Hyebin
Brazee, Patricia L.
Celli, Diego
Flozak, Annette S.
Weng, Anthea
Herrerias, Mariana Maciel
Kryvenko, Vitalii
Vadász, István
Runyan, Constance E.
Abdala Valencia, Hiam
Shigemura, Masahiko
Casalino Matsuda, S. Marina
Misharin, Alexander V.
Budinger, G. R. Scott
Gottardi, Cara J.
Sznajder, Jacob I.
author Dada, Laura Andrea
author_facet Dada, Laura Andrea
Welch, Lynn C.
Magnani, Natalia Daniela
Ren, Ziyou
Han, Hyebin
Brazee, Patricia L.
Celli, Diego
Flozak, Annette S.
Weng, Anthea
Herrerias, Mariana Maciel
Kryvenko, Vitalii
Vadász, István
Runyan, Constance E.
Abdala Valencia, Hiam
Shigemura, Masahiko
Casalino Matsuda, S. Marina
Misharin, Alexander V.
Budinger, G. R. Scott
Gottardi, Cara J.
Sznajder, Jacob I.
author_role author
author2 Welch, Lynn C.
Magnani, Natalia Daniela
Ren, Ziyou
Han, Hyebin
Brazee, Patricia L.
Celli, Diego
Flozak, Annette S.
Weng, Anthea
Herrerias, Mariana Maciel
Kryvenko, Vitalii
Vadász, István
Runyan, Constance E.
Abdala Valencia, Hiam
Shigemura, Masahiko
Casalino Matsuda, S. Marina
Misharin, Alexander V.
Budinger, G. R. Scott
Gottardi, Cara J.
Sznajder, Jacob I.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv HYPERCAPNIA
ALVEOLAR CELLS
PROLIFERATION
topic HYPERCAPNIA
ALVEOLAR CELLS
PROLIFERATION
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.3
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Persistent symptoms and radiographic abnormalities suggestive of failed lung repair are among the most common symptoms in patients with COVID-19 after hospital discharge. In mechanically ventilated patients with acute respiratory distress syndrome (ARDS) secondary to SARS-CoV-2 pneumonia, low tidal volumes to reduce ventilator-induced lung injury necessarily elevate blood CO2 levels, often leading to hypercapnia. The role of hypercapnia on lung repair after injury is not completely understood. Here - using a mouse model of hypercapnia exposure, cell lineage tracing, spatial transcriptomics, and 3D cultures - we show that hypercapnia limits β-catenin signaling in alveolar type II (AT2) cells, leading to their reduced proliferative capacity. Hypercapnia alters expression of major Wnts in PDGFRα+ fibroblasts from those maintaining AT2 progenitor activity toward those that antagonize β-catenin signaling, thereby limiting progenitor function. Constitutive activation of β-catenin signaling in AT2 cells or treatment of organoid cultures with recombinant WNT3A protein bypasses the inhibitory effects of hypercapnia. Inhibition of AT2 proliferation in patients with hypercapnia may contribute to impaired lung repair after injury, preventing sealing of the epithelial barrier and increasing lung flooding, ventilator dependency, and mortality.
Fil: Dada, Laura Andrea. Northwestern University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Welch, Lynn C.. Northwestern University; Estados Unidos
Fil: Magnani, Natalia Daniela. Northwestern University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Ren, Ziyou. Northwestern University; Estados Unidos
Fil: Han, Hyebin. Northwestern University; Estados Unidos
Fil: Brazee, Patricia L.. Northwestern University; Estados Unidos
Fil: Celli, Diego. Northwestern University; Estados Unidos
Fil: Flozak, Annette S.. Northwestern University; Estados Unidos
Fil: Weng, Anthea. Northwestern University; Estados Unidos
Fil: Herrerias, Mariana Maciel. Northwestern University; Estados Unidos
Fil: Kryvenko, Vitalii. Justus Liebig Universitat Giessen.; Alemania
Fil: Vadász, István. Justus Liebig Universitat Giessen.; Alemania
Fil: Runyan, Constance E.. Northwestern University; Estados Unidos
Fil: Abdala Valencia, Hiam. Northwestern University; Estados Unidos
Fil: Shigemura, Masahiko. Northwestern University; Estados Unidos
Fil: Casalino Matsuda, S. Marina. Northwestern University; Estados Unidos
Fil: Misharin, Alexander V.. Northwestern University; Estados Unidos
Fil: Budinger, G. R. Scott. Northwestern University; Estados Unidos
Fil: Gottardi, Cara J.. Northwestern University; Estados Unidos
Fil: Sznajder, Jacob I.. Northwestern University; Estados Unidos
description Persistent symptoms and radiographic abnormalities suggestive of failed lung repair are among the most common symptoms in patients with COVID-19 after hospital discharge. In mechanically ventilated patients with acute respiratory distress syndrome (ARDS) secondary to SARS-CoV-2 pneumonia, low tidal volumes to reduce ventilator-induced lung injury necessarily elevate blood CO2 levels, often leading to hypercapnia. The role of hypercapnia on lung repair after injury is not completely understood. Here - using a mouse model of hypercapnia exposure, cell lineage tracing, spatial transcriptomics, and 3D cultures - we show that hypercapnia limits β-catenin signaling in alveolar type II (AT2) cells, leading to their reduced proliferative capacity. Hypercapnia alters expression of major Wnts in PDGFRα+ fibroblasts from those maintaining AT2 progenitor activity toward those that antagonize β-catenin signaling, thereby limiting progenitor function. Constitutive activation of β-catenin signaling in AT2 cells or treatment of organoid cultures with recombinant WNT3A protein bypasses the inhibitory effects of hypercapnia. Inhibition of AT2 proliferation in patients with hypercapnia may contribute to impaired lung repair after injury, preventing sealing of the epithelial barrier and increasing lung flooding, ventilator dependency, and mortality.
publishDate 2023
dc.date.none.fl_str_mv 2023-01
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/228061
Dada, Laura Andrea; Welch, Lynn C.; Magnani, Natalia Daniela; Ren, Ziyou; Han, Hyebin; et al.; Hypercapnia alters stromal-derived Wnt production limiting β-catenin signaling and proliferation in alveolar type 2 cells; American Society for Clinical Investigation; JCI Insight; 8; 4; 1-2023; 1-38
2379-3708
CONICET Digital
CONICET
url http://hdl.handle.net/11336/228061
identifier_str_mv Dada, Laura Andrea; Welch, Lynn C.; Magnani, Natalia Daniela; Ren, Ziyou; Han, Hyebin; et al.; Hypercapnia alters stromal-derived Wnt production limiting β-catenin signaling and proliferation in alveolar type 2 cells; American Society for Clinical Investigation; JCI Insight; 8; 4; 1-2023; 1-38
2379-3708
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://insight.jci.org/articles/view/159331
info:eu-repo/semantics/altIdentifier/doi/10.1172/jci.insight.159331
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Society for Clinical Investigation
publisher.none.fl_str_mv American Society for Clinical Investigation
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1844613447570948096
score 13.070432

Publicaciones similares