The sodium/glucose cotransporters as potential therapeutic targets for CF lung diseases revealed by human lung organoid swelling assay

Hiroyuki Hirai; Xiubin Liang; Yifei Sun; Yihan Zhang; Jifeng Zhang; Y Eugene Chen; Hongmei Mou; Youyang Zhao; Jie Xu

doi:10.1016/j.omtm.2021.11.008

The sodium/glucose cotransporters as potential therapeutic targets for CF lung diseases revealed by human lung organoid swelling assay

Mol Ther Methods Clin Dev. 2021 Nov 24:24:11-19. doi: 10.1016/j.omtm.2021.11.008. eCollection 2022 Mar 10.

Authors

Hiroyuki Hirai^{1

2}, Xiubin Liang¹, Yifei Sun¹, Yihan Zhang³, Jifeng Zhang¹, Y Eugene Chen¹, Hongmei Mou³, Youyang Zhao², Jie Xu¹

Affiliations

¹ Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, University of Michigan Medical School, 2800 Plymouth Road, Ann Arbor, MI 48109, USA.
² Program for Lung and Vascular Biology, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Division of Critical Care, Department of Pediatrics, Northwestern University Feinberg School of Medicine, 303 E. Superior Street, Chicago, IL 60611, USA.
³ The Mucosal Immunology & Biology Research Center, Massachusetts General Hospital, 55 Fruit Street, Jackson 1402, Boston, MA 02114, USA.

Abstract

Cystic fibrosis (CF) is a lethal autosomal-recessive inherited disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In the present work, we derived human proximal lung organoids (HLOs) from patient-derived pluripotent stem cells (PSCs) carrying disease-causing CFTR mutations. We evaluated the forskolin (Fsk)-stimulated swellings of these HLOs in the presence of CFTR modulators (VX-770 and/or VX-809) and demonstrated that HLOs respond to CFTR modulators in a mutation-dependent manner. Using this assay, we examined the effects of the sodium-dependent glucose cotransporter 1/2 (SGLT1/2) inhibitor drugs phlorizin and sotagliflozin on the basis of our findings that SGLT1 expression is upregulated in CF HLOs and airway epithelial cells compared with their wild-type counterparts. Unexpectedly, both drugs promoted dF/dF HLO swelling. These results reveal SGLTs, especially SGLT1, as potential therapeutic targets for treating CF lung diseases and demonstrate the use of PSC-derived HLOs as a preclinical tool in CF drug development.

Keywords: CFTR; SGLT; cystic fibrosis; drug discovery; human induced pluripotent stem cells (hiPSCs); inhibitor; lung organoids; sodium/glucose cotransporters; sotagliflozin.

Abstract

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