BAL Cell Gene Expression Is Indicative of Outcome and Airway Basal Cell Involvement in Idiopathic Pulmonary Fibrosis

Prasse, Antje; Binder, Harald; Schupp, Jonas C.; Kayser, Gian; Bargagli, Elena; Jaeger, Benedikt; Hess, Moritz; Rittinghausen, Susanne; Vuga, Louis J.; Lynn, Heather; Violette, Shelia M.; Jung, Birgit; Quast, Karsten; Vanaudenaerde, Bart M.; Xu, Yan; Hohlfeld, Jens M.; Krug, Norbert; Herazo-Maya, José D.; Rottoli, Paola; Wuyts, Wim; Kaminski, Naftali

doi:10.1164/rccm.201712-2551oc

Cited by 150 publications

(164 citation statements)

References 30 publications

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“…However, it is not clear whether a similar population in the human airway exists that contributes to metaplastic basal cells, as the airways contain key anatomic differences across the two species. The question of where metaplastic KRT5+ basal cells come from in human IPF has not been answered, but it is clinically significant because the presence of alveolar KRT5+ basal cells directly correlates with mortality in IPF (Prasse et al, 2019). In this study, we made a surprising finding that hAEC2s, but not mAEC2s, can readily transdifferentiate into KRT5+ basal cells in organoid culture and xenotransplant.…”

Section: Introductionmentioning

confidence: 84%

Human alveolar Type 2 epithelium transdifferentiates into metaplastic KRT5+ basal cells during alveolar repair

Kathiriya

Wang

Brumwell

et al. 2020

Preprint

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Understanding differential lineage potential of orthologous stem cells across species can shed light on human disease. Here, utilizing 3D organoids, single cell RNAseq, and xenotransplants, we demonstrate that human alveolar type 2 cells (hAEC2s), unlike murine AEC2s, are multipotent and able to transdifferentiate into KRT5+ basal cells when co-cultured with primary fibroblasts in 3D organoids. Trajectory analyses and immunophenotyping of epithelial progenitors in idiopathic pulmonary fibrosis (IPF) indicate that hAEC2s transdifferentiate into metaplastic basal cells through alveolarbasal intermediate (ABI) cells that we also identify in hAEC2-derived organoids.Modulating hAEC2-intrinsic and niche factors dysregulated in IPF can attenuate metaplastic basal cell transdifferentiation and preserve hAEC2 identity. Finally, hAEC2stransplanted into fibrotic immune-deficient murine lungs engraft as either hAEC2s or differentiated KRT5+ basal cells. Our study indicates that hAEC2s-loss and expansion of alveolar metaplastic basal cells in IPF are causally connected, which would not have been revealed utilizing murine AEC2s as a model. Key wordsHuman stem cells; alveolar type 2 cells (AEC2s); metaplasia; idiopathic pulmonary fibrosis (IPF); KRT5+ basal cells; alveolar-basal intermediate cell (ABI) Highlights •Human AEC2s transdifferentiate into KRT5+ basal cells when accompanied by primary adult human lung mesenchyme in 3D organoid culture.• Alterations of hAEC2-intrinsic and niche factors dysregulated in IPF can modify metaplastic hAEC2 transdifferentiation.• hAEC2s engraft into fibrotic lungs of immune-deficient mice and transdifferentiate into metaplastic basal cells.• Transcriptional trajectory analysis suggests that hAEC2s in IPF gives rise to metaplastic basal cells via alveolar-basal intermediate cells.

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Section: Introductionmentioning

confidence: 84%

Human alveolar Type 2 epithelium transdifferentiates into metaplastic KRT5+ basal cells during alveolar repair

Kathiriya

Wang

Brumwell

et al. 2020

Preprint

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“…Therefore, aberrant CaSR activation in epithelial cells could account for some of the histopathological features of IPF, namely airway epithelial cell hyperplasia within honeycomb cysts, and bronchiolization of distal airways and alveolar spaces. [25] Although many consider alveolar epithelial cells as the initial site of injury in IPF, our study reports an increase in the number of NEBs in the lung of IPF patients. NEBs serve diverse .…”

Section: Discussionmentioning

confidence: 52%

Calcium-sensing receptor antagonism as a novel therapeutic for pulmonary fibrosis

Wolffs

Mansfield

Bruce

et al. 2020

Preprint

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Background: Idiopathic pulmonary fibrosis (IPF) is a disease with very poor prognosis and no curative therapies. The G protein-coupled, calcium/cation-sensing receptor (CaSR) is activated by environmental pollutants and by arginine-derived polyamines, which are thought to play a role in IPF. Whether the CaSR is involved in the pathogenesis of pulmonary fibrosis is unknown. Objective: To investigate the CaSR as a novel drug target for the treatment of pulmonary fibrosis (PF). Methods and results: CaSR protein expression is found in the airway epithelium in the neuroepithelial bodies of the healthy and IPF human lung. Expression of arginine pathway-linked polyamines is increased in PF patient saliva samples compared to non-PF patients. Arginine pathway metabolites, ornithine and spermine, activate the CaSR in primary normal human lung fibroblasts (NHLF), effects prevented by CaSR antagonism using the calcilytic NPS2143. In NHLF calcilytic also reversed the pro-fibrotic effects of exogenous TGFβ1 administration on Rho kinase and αSMA expression, proliferation, collagen production and IL-8 secretion. Targeted CaSR ablation from fibroblasts and smooth muscle cells protects mice from spontaneously occurring, age-related lung fibrosis. Conclusions: Sustained CaSR activation in the lung drives pro-fibrotic processes, which can be reversed by calcilytic. Pharmacological and genetic CaSR blockade reduce both TGFβ1-induced and naturally occurring pro-fibrotic changes. This work provides the scientific rationale for developing inhaled calcilytics as novel therapeutics for IPF.

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“…We found that administration of rhBMP4 is able to promote the repletion of the alveolar epithelium with endogenous SFTPC+ type 2 cells, which also improved gas exchange as seen in the improved oximetry. The ectopic formation of basal cells in the alveoli would likely have an adverse effect on the gas exchange function of the alveoli, which would explain why their presence directly correlates with disease severity in IPF (Prasse et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…This pathological feature denotes the ectopic appearance of proximal bronchus/airway epithelium within the distal lung, characterized by metaplastic KRT5+ basal cells lining cystic airspaces in the alveoli alongside patches of fibroblastic scars (Seibold et al, 2013;Xu et al, 2016). While the functional relationship between metaplasia and scarring is unclear in IPF, the appearance of metaplastic KRT5+ cells is correlated with worsening disease severity and survival (Prasse et al, 2019). This suggests that epithelial metaplasia is a clinically relevant feature of organ fibrosis and a potential therapeutic target.…”

Section: Introductionmentioning

confidence: 99%

Gli1+ mesenchymal stromal cells modulate epithelial metaplasia in lung fibrosis

Cassandras

Wang

Kathiriya

et al. 2019

Preprint

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BAL Cell Gene Expression Is Indicative of Outcome and Airway Basal Cell Involvement in Idiopathic Pulmonary Fibrosis

Abstract: Our results identify and validate a BAL signature that predicts mortality in IPF and improves the accuracy of outcome prediction based on clinical parameters. The BAL signature associated with mortality unmasks a potential role for airway basal cells in IPF.

Cited by 150 publications

References 30 publications

Human alveolar Type 2 epithelium transdifferentiates into metaplastic KRT5+ basal cells during alveolar repair

Human alveolar Type 2 epithelium transdifferentiates into metaplastic KRT5+ basal cells during alveolar repair

Calcium-sensing receptor antagonism as a novel therapeutic for pulmonary fibrosis

Gli1+ mesenchymal stromal cells modulate epithelial metaplasia in lung fibrosis

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