Aging · 2021
A bioinformatic analysis: the overexpression and clinical significance of FCGBP in ovarian cancer.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Wang Kai, Guan Chenan, Shang Xianwen, Ying Xiang, Mei Shuangshuang, Zhu Hanxiao, Xia Liang, Chai Zeying
Аннотация
BACKGROUND: Cystic fibrosis (CF) is a progressive genetic disease characterized by defective ion transport, mucus accumulation, chronic infection, and inflammation that drive airway damage and ultimately end-stage lung failure. Previous studies show that high levels of proteolytic enzymes in the sputum of CF patients correlate with declining lung function, but the related effects on distal lung extracellular matrix (ECM) and immune responses are unclear.
METHODS: To address this gap, induced pluripotent stem cell (iPSC) lines from healthy donors and CF patients were differentiated into macrophages, and stimulated with lipopolysaccharide (LPS) to compare their inflammatory responses. Bulk RNA sequencing, functional assays, and secreted protein profiling revealed key differences between healthy and CF-derived macrophages, providing insight into how these cells may contribute to inflammatory responses in CF patients. Further, human lung ECM from distal CF lung tissue was isolated, used to generate ECM biomaterials, and combined with iPSC-derived macrophages from healthy and CF donors in vitro. Macrophage phenotype was evaluated through cytokine profiling and RNA sequencing.
RESULTS: CF macrophage inflammation was dysregulated, with elevated baseline IL-8, IL-18, and MCP-1 expression, and a blunted inflammatory response to CF ECM compared to healthy macrophages. By using CF ECM and healthy macrophages, we characterized how healthy cells may be altered in a persistent CF milieu after anticipated CFTR modulator therapy.
CONCLUSION: These findings reveal altered innate immune behavior in CF and demonstrate the utility of iPSC-derived macrophages for modeling extrinsic immune-ECM interactions in disease.
METHODS: To address this gap, induced pluripotent stem cell (iPSC) lines from healthy donors and CF patients were differentiated into macrophages, and stimulated with lipopolysaccharide (LPS) to compare their inflammatory responses. Bulk RNA sequencing, functional assays, and secreted protein profiling revealed key differences between healthy and CF-derived macrophages, providing insight into how these cells may contribute to inflammatory responses in CF patients. Further, human lung ECM from distal CF lung tissue was isolated, used to generate ECM biomaterials, and combined with iPSC-derived macrophages from healthy and CF donors in vitro. Macrophage phenotype was evaluated through cytokine profiling and RNA sequencing.
RESULTS: CF macrophage inflammation was dysregulated, with elevated baseline IL-8, IL-18, and MCP-1 expression, and a blunted inflammatory response to CF ECM compared to healthy macrophages. By using CF ECM and healthy macrophages, we characterized how healthy cells may be altered in a persistent CF milieu after anticipated CFTR modulator therapy.
CONCLUSION: These findings reveal altered innate immune behavior in CF and demonstrate the utility of iPSC-derived macrophages for modeling extrinsic immune-ECM interactions in disease.