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 4

Downregulated ZIP8/SIRT1 signaling and decreased renewal capacity of AEC2s from old mouse lungs.

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Downregulated ZIP8/SIRT1 signaling and decreased renewal capacity of AEC...
(A) Flow cytometry analysis to gate out total AEC2s (R2), and ZIP8 expression AEC2s (R3) from lung homologies of young and old mice. (B) Percentage of ZIP8+ cells (R3) within total AEC2s (n = 5–6, **P < 0.01). (C) Number of ZIP8+ cells recovered from young and old mouse lung (n = 5–6, **P < 0.01). (D) CFE of mouse AEC2s isolated from young and old mouse lungs (n = 6–7, **P < 0.01). (E and F) Flow cytometry analysis of ZIP8 expression in gated AEC2s cultured with medium only or medium containing 100 μM ZnSO4 (n = 6, ***P < 0.001). (G–J) 3D organoid culture of AEC2s isolated from lungs of 2.5-, 12-, 14-, and 18-month-old mice with and without 100 μM ZnSO4 treatment. (G) CFE (n = 3–4, *P < 0.05, ***P < 0.001, ****P < 0.0001 by ANOVA). (H–J) Expression of Slc39a8 (H), Sftpc (I), and Pdpn (J) in AEC2s derived from 3D-cultured organoids with and without ZnSO4 treatment by qPCR (n = 3–4, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 by ANOVA). (K) Violin plots of gene expression in AEC2s from lungs of bleomycin-treated young and old mice. (L) IPA pathway analysis of AEC2s from young and old mice on day 4 after bleomycin injury. (M and N) CFE of AEC2s from uninjured 10- to 12-week-old young mice treated with SRT1720 (n = 3–6, **P < 0.01, ****P < 0.0001 by ANOVA) (M) and splitomicin (n = 5–6, ****P < 0.0001 by ANOVA) (N) at the indicated doses and DMSO control. (O) CFE of AEC2s from uninjured 20- to 24-month-old mice treated with SRT1720 at the indicated doses and DMSO control (n = 4, **P < 0.01, ****P < 0.0001 by ANOVA). Data are shown as mean ± SEM. Unpaired 2-tailed Student’s t test.