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Article: Small GTPase RAB6 deficiency promotes alveolar progenitor cell renewal and attenuates PM2.5-induced lung injury and fibrosis

TitleSmall GTPase RAB6 deficiency promotes alveolar progenitor cell renewal and attenuates PM2.5-induced lung injury and fibrosis
Authors
Keywordsadult
aged
animal experiment
animal model
animal tissue
Issue Date2020
PublisherNature Publishing Group: Open Access Journals - Option C. The Journal's web site is located at http://www.nature.com/cddis/index.html
Citation
Cell Death & Disease, 2020, v. 11 n. 10, p. article no. 827 How to Cite?
AbstractIdiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by chronic non-specific inflammation of the interstitial lung and extensive deposition of collagen fibers leading to destruction of lung function. Studies have demonstrated that exposure to fine particulate matter (PM2.5) increases the risk of IPF. In order to recover from PM2.5-induced lung injury, alveolar epithelial cells need to be repaired and regenerated to maintain lung function. Type 2 alveolar epithelial cells (AEC2) are stem cells in the adult lung that contribute to the lung repair process through complex signaling. Our previous studies demonstrated that RAB6, a RAS family member lowly expressed in lung cancer, inhibited lung cancer stem cell self-renewal, but it is unclear whether or not and how RAB6 may regulate AEC2 cell proliferation and self-renewal in PM2.5-induced pulmonary fibrosis. Here, we demonstrated that knockout of RAB6 inhibited pulmonary fibrosis, oxidative stress, and AEC2 cell death in PM2.5-injured mice. In addition, knockout of RAB6 decreased Dickkopf 1(DKK1) autocrine and activated proliferation, self-renewal, and wnt/β-catenin signaling of PM2.5-injured AEC2 cells. RAB6 overexpression increased DKK1 autocrine and inhibited proliferation, self-renewal and wnt/β-catenin signaling in AEC2 cells in vitro. Furthermore, DKK1 inhibitors promoted proliferation, self-renewal and wnt/β-catenin signaling of RAB6 overexpressing AEC2 cells, and attenuated PM2.5-induced pulmonary fibrosis in mice. These data establish RAB6 as a regulator of DKK1 autocrine and wnt/β-catenin signal that serves to regulate AEC2 cell proliferation and self-renewal, and suggest a mechanism that RAB6 disruption may promote AEC2 cell proliferation and self-renewal to enhance lung repair following PM2.5 injury.
Descriptioneid_2-s2.0-85091905539
Persistent Identifierhttp://hdl.handle.net/10722/293250
ISSN
2019 Impact Factor: 6.304
2015 SCImago Journal Rankings: 2.484
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorYang, L-
dc.contributor.authorLiu, G-
dc.contributor.authorLi, X-
dc.contributor.authorXia, Z-
dc.contributor.authorWang, Y-
dc.contributor.authorLin, W-
dc.contributor.authorZhang, W-
dc.contributor.authorZhang, W-
dc.contributor.authorLi, X-
dc.date.accessioned2020-11-23T08:14:01Z-
dc.date.available2020-11-23T08:14:01Z-
dc.date.issued2020-
dc.identifier.citationCell Death & Disease, 2020, v. 11 n. 10, p. article no. 827-
dc.identifier.issn2041-4889-
dc.identifier.urihttp://hdl.handle.net/10722/293250-
dc.descriptioneid_2-s2.0-85091905539-
dc.description.abstractIdiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by chronic non-specific inflammation of the interstitial lung and extensive deposition of collagen fibers leading to destruction of lung function. Studies have demonstrated that exposure to fine particulate matter (PM2.5) increases the risk of IPF. In order to recover from PM2.5-induced lung injury, alveolar epithelial cells need to be repaired and regenerated to maintain lung function. Type 2 alveolar epithelial cells (AEC2) are stem cells in the adult lung that contribute to the lung repair process through complex signaling. Our previous studies demonstrated that RAB6, a RAS family member lowly expressed in lung cancer, inhibited lung cancer stem cell self-renewal, but it is unclear whether or not and how RAB6 may regulate AEC2 cell proliferation and self-renewal in PM2.5-induced pulmonary fibrosis. Here, we demonstrated that knockout of RAB6 inhibited pulmonary fibrosis, oxidative stress, and AEC2 cell death in PM2.5-injured mice. In addition, knockout of RAB6 decreased Dickkopf 1(DKK1) autocrine and activated proliferation, self-renewal, and wnt/β-catenin signaling of PM2.5-injured AEC2 cells. RAB6 overexpression increased DKK1 autocrine and inhibited proliferation, self-renewal and wnt/β-catenin signaling in AEC2 cells in vitro. Furthermore, DKK1 inhibitors promoted proliferation, self-renewal and wnt/β-catenin signaling of RAB6 overexpressing AEC2 cells, and attenuated PM2.5-induced pulmonary fibrosis in mice. These data establish RAB6 as a regulator of DKK1 autocrine and wnt/β-catenin signal that serves to regulate AEC2 cell proliferation and self-renewal, and suggest a mechanism that RAB6 disruption may promote AEC2 cell proliferation and self-renewal to enhance lung repair following PM2.5 injury.-
dc.languageeng-
dc.publisherNature Publishing Group: Open Access Journals - Option C. The Journal's web site is located at http://www.nature.com/cddis/index.html-
dc.relation.ispartofCell Death & Disease-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectadult-
dc.subjectaged-
dc.subjectanimal experiment-
dc.subjectanimal model-
dc.subjectanimal tissue-
dc.titleSmall GTPase RAB6 deficiency promotes alveolar progenitor cell renewal and attenuates PM2.5-induced lung injury and fibrosis-
dc.typeArticle-
dc.identifier.emailXia, Z: zyxia@hkucc.hku.hk-
dc.identifier.authorityXia, Z=rp00532-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1038/s41419-020-03027-2-
dc.identifier.pmid33012781-
dc.identifier.pmcidPMC7533251-
dc.identifier.hkuros319747-
dc.identifier.volume11-
dc.identifier.issue10-
dc.identifier.spagearticle no. 827-
dc.identifier.epagearticle no. 827-
dc.publisher.placeUnited Kingdom-

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