Targeted alveolar regeneration with Frizzled-specific agonists.

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 (Fzd5ag) or Fzd6ag stimulated alveolar epithelial stem cell activity and promoted survival in mice after lung injury, but only Fzd6ag promoted an alveolar fate in airway-derived progenitors. Therefore, we identify a potential strategy for promoting regeneration without exacerbating fibrosis during lung injury. [Display omitted] • Epithelial, endothelial, and stromal cells express different Frizzled (Fzd) genes • Lung AT2 cells and fibroblasts used different Fzds to respond to Wnt ligands • Tetravalent, Fzd-specific agonists enable cell-type-specific Wnt signaling • Fzd5 or Fzd6 agonists promote lung epithelial stem cell activity after bleomycin injury Specific targeting of a Frizzled receptor can induce regeneration of the alveolar epithelium of the mouse lung, showing that the complexity of Wnt-Frizzled combinations in stem cell activation can be disentangled and targeted. [ABSTRACT FROM AUTHOR]