| Literature DB >> 32818433 |
Yi Miao1, Andrew Ha2, Wim de Lau3, Kanako Yuki4, António J M Santos4, Changjiang You5, Maarten H Geurts3, Jens Puschhof3, Cayetano Pleguezuelos-Manzano3, Weng Chuan Peng6, Ramazan Senlice7, Carol Piani7, Jan W Buikema8, Oghenekevwe M Gbenedio9, Mario Vallon4, Jenny Yuan4, Sanne de Haan10, Wieger Hemrika11, Kathrin Rösch12, Luke T Dang13, David Baker13, Melanie Ott12, Philippe Depeille8, Sean M Wu14, Jarno Drost10, Roeland Nusse15, Jeroen P Roose9, Jacob Piehler5, Sylvia F Boj7, Claudia Y Janda16, Hans Clevers17, Calvin J Kuo4, K Christopher Garcia18.
Abstract
Modulation of Wnt signaling has untapped potential in regenerative medicine due to its essential functions in stem cell homeostasis. However, Wnt lipidation and Wnt-Frizzled (Fzd) cross-reactivity have hindered translational Wnt applications. Here, we designed and engineered water-soluble, Fzd subtype-specific "next-generation surrogate" (NGS) Wnts that hetero-dimerize Fzd and Lrp6. NGS Wnt supports long-term expansion of multiple different types of organoids, including kidney, colon, hepatocyte, ovarian, and breast. NGS Wnts are superior to Wnt3a conditioned media in organoid expansion and single-cell organoid outgrowth. Administration of Fzd subtype-specific NGS Wnt in vivo reveals that adult intestinal crypt proliferation can be promoted by agonism of Fzd5 and/or Fzd8 receptors, while a broad spectrum of Fzd receptors can induce liver zonation. Thus, NGS Wnts offer a unified organoid expansion protocol and a laboratory "tool kit" for dissecting the functions of Fzd subtypes in stem cell biology.Entities:
Keywords: DARPin; Frizzled; Wnt; canonical Wnt signaling; organoids; protein engineering; regenerative medicine; stem cell; surrogate Wnt
Year: 2020 PMID： 32818433 PMCID： PMC7655723 DOI： 10.1016/j.stem.2020.07.020
Source DB: PubMed Journal: Cell Stem Cell ISSN： 1875-9777 Impact factor: 24.633