Targeted alveolar regeneration with Frizzled-specific agonists

Ahmad N Nabhan; Joshua D Webster; Jarret J Adams; Levi Blazer; Christine Everrett; Celine Eidenschenk; Alexander Arlantico; Isabel Fleming; Hans D Brightbill; Paul J Wolters; Zora Modrusan; Somasekar Seshagiri; Stephane Angers; Sachdev S Sidhu; Kim Newton; Joseph R Arron; Vishva M Dixit

doi:10.1016/j.cell.2023.05.022

Targeted alveolar regeneration with Frizzled-specific agonists

Cell. 2023 Jul 6;186(14):2995-3012.e15. doi: 10.1016/j.cell.2023.05.022. Epub 2023 Jun 14.

Authors

Ahmad N Nabhan¹, Joshua D Webster², Jarret J Adams³, Levi Blazer³, Christine Everrett⁴, Celine Eidenschenk⁴, Alexander Arlantico⁵, Isabel Fleming⁶, Hans D Brightbill⁵, Paul J Wolters⁷, Zora Modrusan⁸, Somasekar Seshagiri³, Stephane Angers⁹, Sachdev S Sidhu¹⁰, Kim Newton¹¹, Joseph R Arron¹², Vishva M Dixit¹³

Affiliations

¹ Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: nabhana@gene.com.
² Department of Pathology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
³ AntlerA Therapeutics, 348 Hatch Drive, Foster City, CA 94404, USA.
⁴ Department of Molecular Discovery and Cancer Cell Biology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
⁵ Department of Translational Immunology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
⁶ Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
⁷ Department of Medicine, School of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
⁸ Department of Microchemistry, Proteomics, Lipidomics and Next Generation Sequencing, Genentech, South San Francisco, CA 94080, USA.
⁹ AntlerA Therapeutics, 348 Hatch Drive, Foster City, CA 94404, USA; Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 1A2, Canada; Department of Biochemistry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Donnelly Centre, University of Toronto, Toronto, ON M5S 1A8, Canada.
¹⁰ AntlerA Therapeutics, 348 Hatch Drive, Foster City, CA 94404, USA; School of Pharmacy, University of Waterloo, Kitchener, ON N2G 1C5, Canada.
¹¹ Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: knewton@gene.com.
¹² Department of Immunology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
¹³ Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: dixit@gene.com.

PMID: 37321220
DOI: 10.1016/j.cell.2023.05.022

Abstract

Wnt ligands oligomerize Frizzled (Fzd) and Lrp5/6 receptors to control the specification and activity of stem cells in many species. How Wnt signaling is selectively activated in different stem cell populations, often within the same organ, is not understood. In lung alveoli, we show that distinct Wnt receptors are expressed by epithelial (Fzd5/6), endothelial (Fzd4), and stromal (Fzd1) cells. Fzd5 is uniquely required for alveolar epithelial stem cell activity, whereas fibroblasts utilize distinct Fzd receptors. Using an expanded repertoire of Fzd-Lrp agonists, we could activate canonical Wnt signaling in alveolar epithelial stem cells via either Fzd5 or, unexpectedly, non-canonical Fzd6. A Fzd5 agonist (Fzd5^ag) or Fzd6^ag stimulated alveolar epithelial stem cell activity and promoted survival in mice after lung injury, but only Fzd6^ag promoted an alveolar fate in airway-derived progenitors. Therefore, we identify a potential strategy for promoting regeneration without exacerbating fibrosis during lung injury.

Keywords: Frizzled; WNT; alveolus; lung; regeneration.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alveolar Epithelial Cells
Animals
Frizzled Receptors
Lung Injury*
Mice
Stem Cells
Wnt Proteins
Wnt Signaling Pathway

Substances

Wnt Proteins
Frizzled Receptors

Grants and funding

MOP-84273/CIHR/Canada