Taghavifar, F. | bioRxiv Science

bioRxiv2020

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

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.

cell biology↗

bioRxiv2020

Zinc Metabolic Defect of Aging Alveolar Progenitors in Progressive Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a fatal form of interstitial lung disease and aging has been identified as a risk factor to the disease. Alveolar type II cells (AEC2s) function as progenitor cells in the lung. Growing evidences indicate that IPF results from repeating AEC2 injury and inadequate epithelial repair. We previously reported that there was a significant loss of alveolar progenitors in the lungs of patients with IPF. In our current study, we performed single cell RNA-seq of epithelial cells from lungs of patients with IPF and healthy donors as well as epithelial cells from old and young mouse lungs with bleomycin injury. We identified a defect of zinc metabolism of AEC2s from IPF lungs and bleomycin-injured old mouse lungs. We further discovered that a specific zinc transporter ZIP8 was down regulated in IPF AEC2s and AEC2s from aged mice. Loss of ZIP8 expression is associated with impaired AEC2 renewal through sirtuin signaling in aging and IPF. Targeted deletion of Zip8 in murine AEC2 compartment led to reduced AEC2 renewal capacity, impaired AEC2 recovery, and worsened lung fibrosis after bleomycin injury. In summary, we have identified novel metabolic defects of AEC2s during aging and in IPF which contribute to the pathogenesis of lung fibrosis. Therapeutic strategies to restore critical components of these metabolic programs could improve AEC2 progenitor activity and mitigate ongoing fibrogenesis. In BriefLiang et al. performed single cell RNA-seq (scRNA-seq) of epithelial cells in IPF and in mice and discovered a zinc metabolic defect of alveolar progenitor cells (AEC2) in IPF and injured old mice characterized by down-regulation of a specific zinc transporter ZIP8. Manipulation of ZIP8 and zinc in 3D organoid culture of AEC2 in vitro and targeted deletion of Zip8 in AEC2s in vivo demonsrated a role of ZIP8 in promoting AEC2 progenitor function. HighlightsO_LIScRNA-seq revealed dysregulation of zinc metabolism in AEC2s and decreased stem cell signaling in IPF C_LIO_LIReduced SLC39A8 and related gene expression of IPF AEC2s and aged mouse AEC2s C_LIO_LIZIP8-dependent zinc metabolism is required for AEC2 renewal C_LIO_LITargeted deletion of Slc39a8 impaired AEC2 renewal and promoted lung fibrosis C_LI

cell biology↗