Lung Organoids for Hazard Assessment of Nanomaterials

Kastlmeier, Miriam T.; Guenther, Eva M.; Stoeger, Tobias; Voss, Carola

doi:10.3390/ijms232415666

Cited by 9 publications

(4 citation statements)

References 73 publications

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“…Graphics were created with BioRender.com. The manuscript has been published as a preprint on Biorxiv under (Kastlmeier, Rodriguez, et al, 2022).…”

Section: Acknowledgmentsmentioning

confidence: 99%

“…To address knowledge gaps focusing on cytokine driven disease initiating mesenchymal-to-epithelial crosstalk, we used lung organoids derived from human induced pluripotent stem cells (hiPSCs) through chemical directed differentiation. hiPSC-derived alveolar type 2 cells (iAT2s, alveolospheres) are a useful tool to study lung diseases and regeneration, and are recently emerging as New Approach Methodology (NAM) in environmental and occupational hazard assessment (Kastlmeier et al, 2022; Kong et al, 2021). Additionally, alveolospheres recapitulate the characteristic three-dimensional structure of alveoli, holding important functions of the gas exchange area in vitro , wherefore they are a reliable source to study pulmonary disease (Hogan, 2021; Nikolic et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…To address apparent knowledge gaps in the cytokine-driven, disease-relevant mesenchymal-to-epithelial crosstalk, we used lung organoids derived from human induced pluripotent stem cells (hiPSCs) through chemical directed differentiation into a sophisticated co-culture model. hiPSC-derived alveolar type 2 cells (iAT2s) are recognized as a useful tool to study lung diseases and regeneration capacities, and are recently emerging as a novel tool in environmental and occupational hazard assessment (Kastlmeier, Guenther, et al, 2022; Kong et al, 2021). iAT2-derived alveolar organoids recapitulate the characteristic three-dimensional (3D) structure of alveoli and are thereby ideal to mimic important functions of the gas exchange area in vitro .…”

Section: Introductionmentioning

confidence: 99%

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Cytokine signaling converging onIL11in ILD fibroblasts provokes aberrant epithelial differentiation signatures

Kastlmeier

Rodriguez

Cabanis

et al. 2022

Preprint

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Fibrotic interstitial lung disease (ILD) is a group of lung disorders characterized by the accumulation of extracellular matrix, ultimately resulting in the destruction of the pulmonary scaffold. Continuous mesenchyme-derived profibrotic signaling perpetuates the remodeling process, specifically targeting the epithelial cell compartment, thereby destroying the gas exchange area. Studies that address this detrimental crosstalk between lung epithelial cells and fibroblasts are key to understanding ILD.With the aim of identifying functionally relevant targets that drive lung mesenchymal-epithelial crosstalk and their potential as new avenues to therapeutic strategies, we developed a 3D organoid co-culture system based on human induced pluripotent stem cell (hiPSC)-derived alveolar epithelial type 2 cells (iAT2s) and lung fibroblasts from ILD patients as well as IMR-90 controls. While organoid formation capacity and organoid size was comparable in the presence of ILD or control lung fibroblasts, metabolic activity was significantly increased in ILD co-cultures. Alveolar organoids cultured with ILD fibroblasts further demonstrated reduced stem cell function supported by reducedSurfactant Protein C (SFTPC)gene expression together with an aberrant basaloid-prone differentiation program indicated by elevatedCadherin 2 (CDH2), Bone Morphogenic Protein 4 (BMP4)andVimentin (VIM)transcription.In order to identify key mediators of the misguided mesenchymal-to-epithelial crosstalk with a focus on disease-relevant inflammatory processes, we used secretome mass spectrometry to identify key signals secreted by end stage ILD lung fibroblasts. Over 2000 proteins were detected in a single-shot experiment with 47 differentially upregulated proteins when comparing ILD and non-Chronic Lung Disease (CLD) control fibroblasts.The secretome profile was dominated by chemokines of the C-X-C motif family, including CXCL1, CXCL-3, and -8, all interfering with (epithelial) growth factor signaling orchestrated by Interleukin 11 (IL11), steering fibrogenic cell-cell communication, and proteins regulating extracellular matrix remodeling including epithelial-to-mesenchymal transition (EMT). When in turn treating 3D monocultures of iAT2s with IL11 we recapitulated the co-culture results obtained with primary ILD fibroblasts including changes in metabolic activity as well as organoid formation capacity and size.In summary, our analysis identified mesenchyme-derived mediators likely contributing to the disease-perpetuating mesenchymal-to-epithelial crosstalk in ILD by using sophisticated alveolar organoid co-cultures indicating the importance of cytokine-driven aberrant epithelial differentiation and confirmed IL11 as a key player in ILD using an unbiased approach.Abstract Figure

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“…Graphics were created with BioRender.com. The manuscript has been published as a preprint on Biorxiv under (Kastlmeier, Rodriguez, et al, 2022).…”

Section: Acknowledgmentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cytokine signaling converging onIL11in ILD fibroblasts provokes aberrant epithelial differentiation signatures

Kastlmeier

Rodriguez

Cabanis

et al. 2022

Preprint

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“…To address apparent knowledge gaps in the cytokine-driven, disease-relevant mesenchymal-to-epithelial crosstalk, we used lung organoids derived from human induced pluripotent stem cells (hiPSCs) through chemical directed differentiation into a sophisticated co-culture model. hiPSC-derived alveolar type 2 cells (iAT2s) are recognized as a useful tool to study lung diseases and regeneration capacities, and are recently emerging as a novel tool in environmental and occupational hazard assessment ( 11 , 12 ). iAT2-derived alveolar organoids recapitulate the characteristic three-dimensional (3D) structure of alveoli and are thereby ideal to mimic important functions of the gas exchange area in vitro.…”

Section: Introductionmentioning

confidence: 99%

Cytokine signaling converging on IL11 in ILD fibroblasts provokes aberrant epithelial differentiation signatures

et al. 2023

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IntroductionInterstitial lung disease (ILD) is a heterogenous group of lung disorders where destruction and incomplete regeneration of the lung parenchyma often results in persistent architectural distortion of the pulmonary scaffold. Continuous mesenchyme-centered, disease-relevant signaling likely initiates and perpetuates the fibrotic remodeling process, specifically targeting the epithelial cell compartment, thereby destroying the gas exchange area.MethodsWith the aim of identifying functional mediators of the lung mesenchymal-epithelial crosstalk with potential as new targets for therapeutic strategies, we developed a 3D organoid co-culture model based on human induced pluripotent stem cell-derived alveolar epithelial type 2 cells that form alveolar organoids in presence of lung fibroblasts from fibrotic-ILD patients, in our study referring to cases of pulmonary fibrosis, as well as control cell line (IMR-90).ResultsWhile organoid formation capacity and size was comparable in the presence of fibrotic-ILD or control lung fibroblasts, metabolic activity was significantly increased in fibrotic-ILD co-cultures. Alveolar organoids cultured with fibrotic-ILD fibroblasts further demonstrated reduced stem cell function as reflected by reduced Surfactant Protein C gene expression together with an aberrant basaloid-prone differentiation program indicated by elevated Cadherin 2, Bone Morphogenic Protein 4 and Vimentin transcription. To screen for key mediators of the misguided mesenchymal-to-epithelial crosstalk with a focus on disease-relevant inflammatory processes, we used mass spectrometry and characterized the secretome of end stage fibrotic-ILD lung fibroblasts in comparison to non-chronic lung disease (CLD) patient fibroblasts. Out of the over 2000 proteins detected by this experimental approach, 47 proteins were differentially abundant comparing fibrotic-ILD and non-CLD fibroblast secretome. The fibrotic-ILD secretome profile was dominated by chemokines, including CXCL1, CXCL3, and CXCL8, interfering with growth factor signaling orchestrated by Interleukin 11 (IL11), steering fibrogenic cell-cell communication, and proteins regulating extracellular matrix remodeling including epithelial-to-mesenchymal transition. When in turn treating alveolar organoids with IL11, we recapitulated the co-culture results obtained with primary fibrotic-ILD fibroblasts including changes in metabolic activity.ConclusionWe identified mediators likely contributing to the disease-perpetuating mesenchymal-to-epithelial crosstalk in ILD. In our alveolar organoid co-cultures, we were able to highlight the importance of fibroblast-initiated aberrant epithelial differentiation and confirmed IL11 as a key player in fibrotic-ILD pathogenesis by unbiased fibroblast secretome analysis.

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