Bronchioalveolar stem cells in lung repair, regeneration and disease

Jones‐Freeman, Bernadette; Starkey, Malcolm R.

doi:10.1002/path.5527

Cited by 22 publications

(25 citation statements)

References 63 publications

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“…S2A and E). Despite emerging roles of bronchioalveolar stem cells (BASCs, CC10 + SPC + ), which contribute to the maintenance of bronchiolar club cells and alveolar epithelial cells [36], and promote lung regeneration upon infection of influenza virus [37] and naphthalene-induced airway injury [38], no activation of the Wnt signaling was detected in BACS cells [36] upon smoke exposure in this study (Fig. S3F), possibly due to sparsity of BASCs captured in lung sections.…”

Section: Depletion Of Fam13a Activates Wnt Signaling In Both Club Cells and Atii Cells After Cs Exposurementioning

confidence: 75%

“…However, in response to a mild injury stimulus such as CS exposure, it remains unclear whether Club cells could serve as epithelial stem cells facilitating alveolar repair. Basal cells [52] and BASCs [36,38] have also been reported as stem cells in murine lungs to contribute to repair/regeneration during lung homeostasis and injury. Especially, BASCs contribute to regeneration of both airway and alveolar epithelium.…”

Section: Discussionmentioning

confidence: 99%

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Tempo-spatial regulation of the Wnt pathway by FAM13A modulates the stemness of alveolar epithelial progenitors

Lin

Gong

et al. 2021

eBioMedicine

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Background: Family with Sequence Similarity 13, Member A (FAM13A) gene has been consistently associated with COPD by Genome-wide association studies (GWAS). Our previous study demonstrated that FAM13A was mainly expressed in the lung epithelial progenitors including Club cells and alveolar type II epithelial (ATII) cells. Fam13a À/À mice were resistant to cigarette smoke (CS)Àinduced emphysema through promoting b-catenin/Wnt activation. Given the important roles of b-catenin/Wnt activation in alveolar regeneration during injury, it is unclear when and where FAM13A regulates the Wnt pathway, the requisite pathway for alveolar epithelial repair, in vivo during CS exposure in lung epithelial progenitors. Methods: Fam13a +/+ or Fam13a À/À mice were crossed with TCF/Lef:H2B-GFP Wnt-signaling reporter mouse line to indicate b-catenin/Wnt-activated cells labeled with GFP followed by acute (1 month) or chronic (7 months) CS exposure. Fluorescence-activated flow cytometry analysis, immunofluorescence and organoid culture system were performed to identify the b-catenin/Wnt-activated cells in Fam13a +/+ or Fam13a À/À mice exposed to CS. Fam13a;SftpcCreERT2;Rosa26RmTmG mouse line, where GFP labels ATII cells, was generated for alveolar organoid culture followed by analyses of organoid number, immunofluorescence and gene expression. Single cell RNA-seq data from COPD ever smokers and nonsmoker control lungs were further analyzed. Findings: We found that FAM13A-deficiency significantly increased Wnt activation mainly in lung epithelial cells. Consistently, after long-term CS exposure in vivo, FAM13A deficiency bestows alveolar epithelial progenitor cells with enhanced proliferation and differentiation in the ex vivo organoid model. Importantly, expression of FAM13A is significantly increased in human COPD-derived ATII cells compared to healthy ATII cells as suggested by single cell RNA-sequencing data. Interpretation: Our findings suggest that FAM13A-deficiency promotes the Wnt pathway-mediated ATII cell repair/regeneration, and thereby possibly mitigating CS-induced alveolar destruction. Fund: This project is funded by the National Institutes of Health of United States of America (NIH) grants R01HL127200, R01HL137927, R01HL148667 and R01HL147148 (XZ).

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Section: Depletion Of Fam13a Activates Wnt Signaling In Both Club Cells and Atii Cells After Cs Exposurementioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Tempo-spatial regulation of the Wnt pathway by FAM13A modulates the stemness of alveolar epithelial progenitors

Lin

Gong

et al. 2021

eBioMedicine

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“…Recent studies have concentrated on the potential of stem cells for the treatment of lung-associated diseases, including RILI [ 6 – 8 ]. In addition, radiation resistance and potential regeneration capacity have been defined as traits of stem cells in mouse models [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Sox9-expressing cells promote regeneration after radiation-induced lung injury via the PI3K/AKT pathway

Chen

Zhong

et al. 2021

Stem Cell Res Ther

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Background Radiation-induced lung injury (RILI) is considered one of the most common complications of thoracic radiation. Recent studies have focused on stem cell properties to obtain ideal therapeutic effects, and Sox9 has been reported to be involved in stem cell induction and differentiation. However, whether Sox9-expressing cells play a role in radiation repair and regeneration remains unknown. Methods We successfully obtained Sox9CreER, RosatdTomato and RosaDTA mice and identified Sox9-expressing cells through lineage tracing. Then, we evaluated the effects of the ablation of Sox9-expressing cells in vivo. Furthermore, we investigated the underlying mechanism of Sox9-expressing cells during lung regeneration via an online single-cell RNA-seq dataset. Results In our study, we demonstrated that Sox9-expressing cells promote the regeneration of lung tissues and that ablation of Sox9-expressing cells leads to severe phenotypes after radiation damage. In addition, analysis of an online scRNA-Seq dataset revealed that the PI3K/AKT pathway is enriched in Sox9-expressing cells during lung epithelium regeneration. Finally, the AKT inhibitor perifosine suppressed the regenerative effects of Sox9-expressing cells and the AKT pathway agonist promotes proliferation and differentiation. Conclusions Taken together, the findings of our study suggest that Sox9-expressing cells may serve as a therapeutic target in lung tissue after RILI.

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“…Thyroid transcription factor 1 (TTF-1), also known as NKX2-1, is a member of the highly conserved homeodomain-containing transcription factor family, which activates the expression of selected genes in the lung and thyroid, as well as a restricted part of the brain, and is essential for the development and differentiation of these organs [1][2][3]. The cellular mechanisms regulating lung homeostasis are not completely understood; however, different epithelial regions and compartments in the lung are known to be maintained by distinct resident stem cell populations [4]. Notably, a series of peripheral lung cells defined as the terminal respiratory unit (TRU), in which gas exchange occurs, is under the control of NKX2-1/TTF-1 [5].…”

Section: Introductionmentioning

confidence: 99%

Transcription start site‐level expression of thyroid transcription factor 1 isoforms in lung adenocarcinoma and its clinicopathological significance

Sano

Hayashi

Suehara

et al. 2021

The Journal of Pathology CR

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There are multiple transcription start sites (TSSs) in agreement with multiple transcript variants encoding different isoforms of NKX2-1/TTF-1 (thyroid transcription factor 1); however, the clinicopathological significance of each transcript isoform of NKX2-1/TTF-1 in lung adenocarcinoma (LAD) is unknown. Herein, TSS-level expression of NKX2-1/TTF-1 isoforms was evaluated in 71 LADs using bioinformatic analysis of cap analysis of gene expression (CAGE)-sequencing data, which provides genome-wide expression levels of the 5'-untranslated regions and the TSSs of different isoforms. Results of CAGE were further validated in 664 LADs using in situ hybridisation. Fourteen of 17 TSSs in NKX2-1/TTF-1 (80% of known TSSs in FANTOM5, an atlas of mammalian promoters) were identified in LADs, including TSSs 1-13 and 15; four isoforms of NKX2-1/TTF-1 transcripts (NKX2-1_001, NKX2-1_002, NKX2-1_004, and NKX2-1_005) were expressed in LADs, although NKX2-1_005 did not contain a homeodomain. Among those, six TSSs regulated NKX2-1_004 and NKX2-1_005, both of which contain exon 1. LADs with low expression of isoforms from TSS region 11 regulating exon 1 were significantly associated with poor prognosis in the CAGE data set. In the validation set, 62 tumours (9.3%) showed no expression of NKX2-1/TTF-1 exon 1; such tumours were significantly associated with older age, EGFR wild-type tumours, and poor prognosis. In contrast, 94 tumours, including 22 of 30 pulmonary invasive mucinous adenocarcinomas (IMAs) exhibited exon 1 expression without immunohistochemical TTF-1 protein expression. Furthermore, IMAs commonly exhibited higher exon 1 expression relative to that of exon 4/5, which contained a homeodomain in comparison with EGFR-mutated LADs. These transcriptome and clinicopathological results reveal that LAD use at least 80% of NKX2-1 TSSs and expression of the NKX2-1/TTF-1 transcript isoform without exon 1 (NKX2-1_004 and NKX2-1_005) defines a distinct subset of LAD characterised by aggressive behaviour in elder patients. Moreover, usage of alternative TSSs regions regulating NKX2-1_005 may occur in subsets of LADs.

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Bronchioalveolar stem cells in lung repair, regeneration and disease

Cited by 22 publications

References 63 publications

Tempo-spatial regulation of the Wnt pathway by FAM13A modulates the stemness of alveolar epithelial progenitors

Tempo-spatial regulation of the Wnt pathway by FAM13A modulates the stemness of alveolar epithelial progenitors

Sox9-expressing cells promote regeneration after radiation-induced lung injury via the PI3K/AKT pathway

Transcription start site‐level expression of thyroid transcription factor 1 isoforms in lung adenocarcinoma and its clinicopathological significance

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