Browse
Submit Data
Databases
API
Help

Dataset Information

22 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Generation of macrophage containing alveolar organoids derived from human pluripotent stem cells for pulmonary fibrosis modeling and drug efficacy testing.

ABSTRACT: Macrophages are a central immune component in various types of in vitro human organoid systems to recapitulate normal and pathological development. However, to date, generation of human alveolar organoids (AOs) containing macrophages for use as a pulmonary fibrosis (PF) model and drug efficacy evaluation has not been reported. Here, we generated multicellular alveolar organoids (Mac-AOs) containing functional macrophages derived from human pluripotent stem cells based on stepwise direct differentiation by mimicking developmental cues in a temporally controlled manner. Derived Mac-AOs contained the expected range of cell types, including alveolar progenitors, mesenchymal cells, alveolar epithelial cells (type 1 and 2), and macrophages. Treatment with transforming growth factor (TGF-β1) induced inflammation and fibrotic changes in Mac-AOs, offering a PF model for validating the therapeutic potential of new drugs. TGF-β1-induced fibrotic responses and collagen accumulation in these Mac-AOs were effectively ameliorated by treatment with Pirfenidone, Nintedanib, and NP-011 via suppression of extracellular signal-regulated kinase signaling. To the best of our knowledge, this is the first report to provide non-epithelial functional macrophage-containing human AO system, which will better recapitulate the complexity of in vivo alveolar tissues and advance our understanding of the pathogenesis and development of effective therapies for PF.

SUBMITTER: Heo HR

PROVIDER: S-EPMC8684607 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Human pluripotent stem-cell-derived alveolar organoids for modeling pulmonary fibrosis and drug testing.

Project description:Detailed understanding of the pathogenesis and development of effective therapies for pulmonary fibrosis (PF) have been hampered by lack of in vitro human models that recapitulate disease pathophysiology. In this study, we generated alveolar organoids (AOs) derived from human pluripotent stem cells (hPSCs) for use as an PF model and for drug efficacy evaluation. Stepwise direct differentiation of hPSCs into alveolar epithelial cells by mimicking developmental cues in a temporally controlled manner was used to generate multicellular AOs. Derived AOs contained the expected spectrum of differentiated cells, including alveolar progenitors, type 1 and 2 alveolar epithelial cells and mesenchymal cells. Treatment with transforming growth factor (TGF-β1) induced fibrotic changes in AOs, offering a PF model for therapeutic evaluation of a structurally truncated form (NP-011) of milk fat globule-EGF factor 8 (MFG-E8) protein. The significant fibrogenic responses and collagen accumulation that were induced by treatment with TGF-β1 in these AOs were effectively ameliorated by treatment with NP-011 via suppression of extracellular signal-regulated kinase (ERK) signaling. Furthermore, administration of NP-011 reversed bleomycin-induced lung fibrosis in mice also via ERK signaling suppression and collagen reduction. This anti-fibrotic effect mirrored that following Pirfenidone and Nintedanib administration. Furthermore, NP-011 interacted with macrophages, which accelerated the collagen uptake for eliminating accumulated collagen in fibrotic lung tissues. This study provides a robust in vitro human organoid system for modeling PF and assessing anti-fibrotic mechanisms of potential drugs and suggests that modified MGF-E8 protein has therapeutic potential for treating PF.

| S-EPMC7961057 | biostudies-literature

Disease modeling of pulmonary fibrosis using human pluripotent stem cell-derived alveolar organoids.

Project description:Although alveolar epithelial cells play a critical role in the pathogenesis of pulmonary fibrosis, few practical in vitro models exist to study them. Here, we established a novel in vitro pulmonary fibrosis model using alveolar organoids consisting of human pluripotent stem cell-derived alveolar epithelial cells and primary human lung fibroblasts. In this human model, bleomycin treatment induced phenotypes such as epithelial cell-mediated fibroblast activation, cellular senescence, and presence of alveolar epithelial cells in abnormal differentiation states. Chemical screening performed to target these abnormalities showed that inhibition of ALK5 or blocking of integrin αVβ6 ameliorated the fibrogenic changes in the alveolar organoids. Furthermore, organoid contraction and extracellular matrix accumulation in the model recapitulated the pathological changes observed in pulmonary fibrosis. This human model may therefore accelerate the development of highly effective therapeutic agents for otherwise incurable pulmonary fibrosis by targeting alveolar epithelial cells and epithelial-mesenchymal interactions.

| S-EPMC8693665 | biostudies-literature

Pulmonary fibrosis model using micro-CT analyzable human PSC-derived alveolar organoids containing alveolar macrophage-like cells.

Project description:Human lung organoids (hLOs) are useful for disease modelling and drug screening. However, a lack of immune cells in hLOs limits the recapitulation of in vivo cellular physiology. Here, we generated hLOs containing alveolar macrophage (AMφ)-like cells derived from pluripotent stem cells (PSC). To bridge hLOs with advanced human lung high-resolution X-ray computed tomography (CT), we acquired quantitative micro-CT images. Three hLO types were observed during differentiation. Among them, alveolar hLOs highly expressed not only lung epithelial cell markers but also AMφ-specific markers. Furthermore, CD68+ AMφ-like cells were spatially organized on the luminal epithelial surface of alveolar hLOs. Bleomycin-treated alveolar hLOs showed upregulated expression of fibrosis-related markers and extracellular matrix deposits in the alveolar sacs. Alveolar hLOs also showed structural alterations such as excessive tissue fraction under bleomycin treatment. Therefore, we suggest that micro-CT analyzable PSC-derived alveolar hLOs are a promising in vitro model to predict lung toxicity manifestations, including fibrosis.

| S-EPMC8907399 | biostudies-literature

Modeling of Aberrant Epithelial Reprogramming in Idiopathic Pulmonary Fibrosis using Human Induced Pluripotent Stem Cell-derived Alveolar Organoids

Project description:Alveolar type 2 (AT2) organoids, derived from induced pluripotent stem cells, were stimulated with a fibrosis cocktail containing the pro-fibrotic and inflammatory cytokines TGF-β (5 ng/ml), TNF-α (10 ng/ml), PDGF-AB (10 ng/ml) and LPA (5 μM) or control cocktail containing diluents for 72 h.

2023-05-22 | E-MTAB-11676 | biostudies-arrayexpress

Disease modeling of pulmonary fibrosis using human iPS cell-derived alveolar organoids

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-11-19 | GSE172123 | GEO

Impairment of alveolar macrophage transcription in idiopathic pulmonary fibrosis.

Project description:Alveolar macrophages are inflammatory cells that may contribute to the pathogenesis of idiopathic pulmonary fibrosis (IPF), which is characterized by excessive alveolar aggregation of cells and extracellular matrix proteins.To identify potential molecular mechanisms of IPF.To examine large-scale gene expression, messenger RNA isolated from alveolar macrophages and peripheral blood mononuclear cells from subjects with IPF and normal volunteers was hybridized to cDNA filters.We showed that in IPF there is global down-regulation of gene expression in alveolar macrophages but not in blood monocytes. Nuclear run-on and pulse-chase studies showed that alveolar macrophages had significantly reduced transcription (p < 0.01). No significant difference in RNA degradation was found between subjects with IPF and normal volunteers. Western blot analyses revealed that concentrations of transcription factor II-H, a general transcription factor, were significantly lower in alveolar macrophages from subjects with IPF than in those from normal volunteers (p = 0.012).Impaired transcription in IPF is associated with decreased concentrations of transcription factor II-H in alveolar macrophages and may alter the intraalveolar milieu in IPF.

| S-EPMC1899274 | biostudies-other

Disease modeling of pulmonary fibrosis using human iPS cell-derived alveolar organoids (fibroblasts)

Project description:We developed an in vitro model of pulmonary fibrosis using alveolar organoids, consisting of human induced pluripotent stem cell-derived alveolar epithelial cells and human lung fibroblasts. In this model, fibroblasts were activated by bleomysin (BLM) treatment in an epithelial cell-dependent manner simillar to the pathogenic mechanism of pulmonary fibrosis.

2021-11-19 | GSE172121 | GEO

Disease modeling of pulmonary fibrosis using human iPS cell-derived alveolar organoids (SPC+ cells)

2021-11-19 | GSE172122 | GEO

Monocyte-derived alveolar macrophage apolipoprotein E participates in pulmonary fibrosis resolution.

Project description:Recent studies have presented compelling evidence that it is not tissue-resident, but rather monocyte-derived alveolar macrophages (TR-AMs and Mo-AMs, respectively) that are essential to development of experimental lung fibrosis. However, whether apolipoprotein E (ApoE), which is produced abundantly by Mo-AMs in the lung, plays a role in the pathogenesis is unclear. In this study, we found that pulmonary ApoE was almost exclusively produced by Mo-AMs in mice with bleomycin-induced lung fibrosis. We showed that, although ApoE was not necessary for developing maximal fibrosis in bleomycin-injured lung, it was required for the resolution of this pathology. We found that ApoE directly bound to Collagen I and mediated Collagen I phagocytosis in vitro and in vivo, and this process was dependent on low-density lipoprotein receptor-related protein 1 (LPR1). Furthermore, interference of ApoE/LRP1 interaction impaired the resolution of lung fibrosis in bleomycin-treated WT mice. In contrast, supplementation of ApoE promoted this process in ApoE-/- animals. In conclusion, Mo-AM-derived ApoE is beneficial to the resolution of lung fibrosis, supporting the notion that Mo-AMs may have distinct functions in different phases of lung fibrogenesis. The findings also suggest a potentially novel therapeutic target for treating lung fibrosis, to which effective remedies remain scarce.

| S-EPMC7141408 | biostudies-literature

Alveolar Macrophage Gene Expression in Human Pulmonary Fibrosis

Project description:Gene expression profiles for patients affected with Sporadic and Familial Pulmonary Fibrosis.

2014-06-30 | GSE49072 | GEO