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Pulmonary microvascular endothelial cells support alveolar epithelial growth via bone morphogenetic protein 6 secretion

ABSTRACT: Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation and emphysema development, associated with enhanced tissue destruction and defective repair. Supporting cells in the alveolar niche play a crucial role in guiding the activation of alveolar epithelial progenitor cells during repair. Despite their close anatomical proximity, understanding of the supportive role of the pulmonary microvascular endothelium in adult alveolar epithelial repair remains limited. We hypothesized that angiocrine factors secreted by pulmonary endothelial cells support alveolar epithelial cell growth. Here, we report that human pulmonary microvasculature endothelial cells (HPMECs) support murine and human alveolar organoid formation through paracrine signaling via the secretion of extracellular vesicles and soluble factors. Transcriptomic and proteomic analysis pinpointed HPMEC-derived bone morphogenetic protein 6 (BMP6) as a critical factor for alveolar organoid formation. BMP6 deficiency was associated with reduced Wnt signaling and augmented oxidative stress signaling in murine lung tissue. Furthermore, BMP6 promoted alveolar epithelial cell growth, whereas function-blocking antibodies targeting BMP6 inhibited the beneficial effect of endothelial cells on murine alveolar organoid formation. Taken together, our findings highlight BMP6 as a key regulator of adult epithelial repair and suggest its potential as a therapeutic target for lung repair, particularly in individuals with COPD.

ORGANISM(S): Mus musculus

PROVIDER: GSE271971 | GEO | 2025/02/01

REPOSITORIES: GEO

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Project description:Fibrotic interstitial lung disease (ILD) are lung disorders characterized by the accumulation of extracellular matrix, ultimately resulting in the destruction of the pulmonary scaffold. Continuous pro-fibrotic 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 mesenchymal-epithelial crosstalk and their potential as new avenues to therapeutic strategies, we developed an organoid co-culture system based on human induced pluripotent stem cell-derived alveolar epithelial type 2 cells 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 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. 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 control fibroblasts. The secretome profile was dominated by chemokines of the C-X-C motif family, including CXCL1, -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. 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.

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Pulmonary microvascular endothelial cells support alveolar epithelial growth via bone morphogenetic protein 6 secretion

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