The ZIP8/SIRT1 axis regulates alveolar progenitor cell renewal in aging and idiopathic pulmonary fibrosis
Jiurong Liang, Guanling Huang, Xue Liu, Forough Taghavifar, Ningshan Liu, Yizhou Wang, Nan Deng, Changfu Yao, Ting Xie, Vrishika Kulur, Kristy Dai, Ankita Burman, Simon C. Rowan, S. Samuel Weigt, John Belperio, Barry Stripp, William C. Parks, Dianhua Jiang, Paul W. Noble
Jiurong Liang, Guanling Huang, Xue Liu, Forough Taghavifar, Ningshan Liu, Yizhou Wang, Nan Deng, Changfu Yao, Ting Xie, Vrishika Kulur, Kristy Dai, Ankita Burman, Simon C. Rowan, S. Samuel Weigt, John Belperio, Barry Stripp, William C. Parks, Dianhua Jiang, Paul W. Noble
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Research Article Pulmonology

The ZIP8/SIRT1 axis regulates alveolar progenitor cell renewal in aging and idiopathic pulmonary fibrosis

Abstract

Type 2 alveolar epithelial cells (AEC2s) function as progenitor cells in the lung. We have shown previously that failure of AEC2 regeneration results in progressive lung fibrosis in mice and is a cardinal feature of idiopathic pulmonary fibrosis (IPF). In this study, we identified deficiency of a specific zinc transporter, SLC39A8 (ZIP8), in AEC2s from both IPF lungs and lungs of old mice. Loss of ZIP8 expression was associated with impaired renewal capacity of AEC2s and enhanced lung fibrosis. ZIP8 regulation of AEC2 progenitor function was dependent on SIRT1. Replenishment with exogenous zinc and SIRT1 activation promoted self-renewal and differentiation of AEC2s from lung tissues of IPF patients and old mice. Deletion of Zip8 in AEC2s in mice resulted in impaired AEC2 renewal, increased susceptibility to bleomycin injury, and development of spontaneous lung fibrosis. Therapeutic strategies to restore zinc metabolism and appropriate SIRT1 signaling could improve AEC2 progenitor function and mitigate ongoing fibrogenesis.

Authors

Jiurong Liang, Guanling Huang, Xue Liu, Forough Taghavifar, Ningshan Liu, Yizhou Wang, Nan Deng, Changfu Yao, Ting Xie, Vrishika Kulur, Kristy Dai, Ankita Burman, Simon C. Rowan, S. Samuel Weigt, John Belperio, Barry Stripp, William C. Parks, Dianhua Jiang, Paul W. Noble

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Figure 5

Targeted deletion of Slc39a8 decreased AEC2 renewal.

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Targeted deletion of Slc39a8 decreased AEC2 renewal. (A) ZIP-expressing ...
(A) ZIP-expressing cells among gated AEC2s and (B) percentage of ZIP8+ cells within the total AEC2 population from uninjured Zip8AEC2 and control mice by flow cytometry (n = 8, ****P < 0.001). (C and D) Intracellular zinc levels of AEC2s (C) and percentage of zinc+ AEC2s within the total AEC2 population (D) from Zip8AEC2 (n = 4) and control mice (n = 8) by flow cytometry (**P < 0.01). (E) CFE of flow-sorted AEC2s from uninjured Zip8AEC2 and control mice with 3D organoid culture (n = 6 each, *P < 0.05). (F and G) Expression of Sirt1 (n = 4, *P < 0.05) (F) and Pdpn (n = 5, **P < 0.01) (G) in AEC2s derived from 3D-cultured organoids. (H–J) AEC2s from day 4 bleomycin-injured Zip8AEC2 and control mice. (H) Number of AEC2s recovered per lung (n = 5, ***P < 0.001). (I and J) CFE of AEC2s with 3D organoid culture (n = 5–7, **P < 0.01) (I) and colony size (n = 28–86, ****P < 0.0001) (J). (K and L) Ki-67 expression by flow cytometry (n = 6 each, *P < 0.05) (K) and Pdpn expression by qPCR (n = 5 each, ****P < 0.0001) (L) in AEC2s derived from 3D-cultured organoids. (M and N) Violin plots of gene expression in AEC2s with scRNA-Seq. (M) AEC2s from 2-month-old (Young) and 18- to 20-month-old (Old) C57BL/6 WT mice (n = 3). (N) AEC2s from 10- to 12-week-old (young) Zip8AEC2 mice and littermate controls 2 weeks after 4 doses of tamoxifen injection. Data are shown as mean ± SEM. Unpaired 2-tailed Student’s t test.