Single-Cell Transcriptomics Identifies Dysregulated Metabolic Programs of Aging Alveolar Progenitor Cells in Lung Fibrosis

Liang, J.; Huang, G.; Liu, X.; Taghavifar, F.; Liu, N.; Yao, C.; Deng, N.; Wangy, Y.; Burman, A.; Xie, T.; Rowan, S. C.; Chen, P.; Hogaboam, C. M.; Stripp, B.; Weigt, S. S.; Belperio, J.; Park, W.; Noble, P. W.; Jiang, D.

doi:10.1101/2020.07.30.227892

bioRxiv · 10.1101/2020.07.30.227892

Single-Cell Transcriptomics Identifies Dysregulated Metabolic Programs of Aging Alveolar Progenitor Cells in Lung Fibrosis

Liang, J.·Huang, G.·Liu, X.·Taghavifar, F.·Liu, N.·Yao, C.·Deng, N.·Wangy, Y.·Burman, A.·Xie, T.·Rowan, S. C.·Chen, P.·Hogaboam, C. M.·Stripp, B.·Weigt, S. S.·Belperio, J.·Park, W.·Noble, P. W.·Jiang, D.

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Abstract

Aging is a critical risk factor in progressive lung fibrotic diseases such as idiopathic pulmonary fibrosis (IPF). Loss of integrity of type 2 alveolar epithelial cells (AEC2s) is the main causal event in the pathogenesis of IPF. To systematically examine the genomic program changes of AEC2s with aging and lung injury, we performed unbiased single cell RNA-seq analyses of lung epithelial cells from either uninjured or bleomycin-injured young and old mice. Major lung epithelial cell types were readily identified with canonical cell markers in our dataset. Heterogenecity of AEC2s was apparent, and AEC2s were then classified into three subsets according to their gene signatures. Genes related to lipid metabolism and glycolysis were significantly altered within these three clusters of AEC2s, and also affected by aging and lung injury. Importantly, IPF AEC2s showed similar genomic programming and metabolic changes as that of AEC2s from bleomycin injured old mouse lungs relative to controls. Furthermore, perturbation of both lipid metabolism and glycolysis significantly changed progenitor renewal capacity in 3-Demensional organoid culture of AEC2s. Taken togather, this work identified metabolic defects of AEC2s in aging and during lung injury. Strategies to rectify these altered programs would promote AEC2 renewal which in turn improves lung repair. One sentence summaryMetabolic defects of alveolar progenitors in aging and during lung injury impair their renewal.

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Liang, J., Huang, G., Liu, X., Taghavifar, F., Liu, N., Yao, C., Deng, N., Wangy, Y., Burman, A., Xie, T., Rowan, S. C., Chen, P., Hogaboam, C. M., Stripp, B., Weigt, S. S., Belperio, J., Park, W., Noble, P. W., Jiang, D.. 2020-07-30. Single-Cell Transcriptomics Identifies Dysregulated Metabolic Programs of Aging Alveolar Progenitor Cells in Lung Fibrosis. https://doi.org/10.1101/2020.07.30.227892

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