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 3

ZIP8-dependent zinc metabolism regulates AEC2 renewal through SIRT1.

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ZIP8-dependent zinc metabolism regulates AEC2 renewal through SIRT1. (A)...
(A) IPA pathway analysis of AEC2s from healthy and IPF lungs.(B) Sirtuin activation score of healthy and IPF AEC2s. (C and D) SIRT1 expression in freshly isolated AEC2s (C) and AEC2s derived from 3D organoids (D) by qPCR (n = 4–6, *P < 0.05). (E) SIRT1 expression of AEC2s derived from 3D-cultured organoids of ZIP8+ and ZIP8– AEC2s (n = 5 each, *P < 0.05). (F) Intracellular SIRT1 levels in healthy and IPF AEC2s without and with ZnSO4 treatment by flow cytometry (n = 3–4). (G) Intracellular SIRT1 levels in gated ZIP8+ and ZIP8– AEC2s from healthy lungs (n = 4). (H and I) CFE with 3D organoid culture of AEC2s from healthy lungs treated with either 1 μM SRT1720 (n = 4–5, ***P < 0.001 by ANOVA) (H) or 125 and 200 μM splitomicin (n = 3, ***P < 0.001, ****P < 0.0001 by ANOVA) (I). (J) CFE of AEC2s from IPF lungs cultured with SRT1720 at the indicated concentrations (n = 3, **P < 0.01, ****P < 0.0001 by ANOVA). (K) CFE of AEC2s from IPF lungs cultured with 1 μM SRT1720, 100 μM ZnSO4, or both (n = 3–4, ****P < 0.0001 by ANOVA). (L–N) A549 cells with SIRT1 knockout and control cells. SIRT1 ko 1, set 1 sgRNA; SIRT ko 2, set 2 sgRNA. (L) SIRT1 expression by qPCR. (M) SIRT1 expression by Western blot analysis; the same experiments were performed 3 times. (N) CFE with 3D organoid culture (n = 4, ***P < 0.001 by ANOVA). Data are shown as mean ± SEM. Unpaired 2-tailed Student’s t test.