Next-Generation Surrogate Wnts Support Organoid Growth and Deconvolute Frizzled Pleiotropy In Vivo
Miao, Yi; Ha, Andrew; de Lau, Wim; Yuki, Kanako; Santos, António J M; You, Changjiang; Geurts, Maarten H; Puschhof, Jens; Pleguezuelos-Manzano, Cayetano; Peng, Weng Chuan; Senlice, Ramazan; Piani, Carol; Buikema, Jan W; Gbenedio, Oghenekevwe M; Vallon, Mario; Yuan, Jenny; de Haan, Sanne; Hemrika, Wieger; Rösch, Kathrin; Dang, Luke T; Baker, David; Ott, Melanie; Depeille, Philippe; Wu, Sean M; Drost, Jarno; Nusse, Roeland; Roose, Jeroen P; Piehler, Jacob; Boj, Sylvia F; Janda, Claudia Y; Clevers, Hans; Kuo, Calvin J; Garcia, K Christopher
(2020) Cell stem cell, volume 27, issue 5, pp. 840 - 851.e6
(Article)
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
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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.
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Keywords: DARPin, Frizzled, Wnt, canonical Wnt signaling, organoids, protein engineering, regenerative medicine, stem cell, surrogate Wnt, Molecular Medicine, Genetics, Cell Biology
ISSN: 1934-5909
Publisher: Cell Press
Note: Funding Information: We acknowledge Georg Busslinger and Else Driehuis for establishing and providing stomach and pancreas organoid cultures, respectively. This work is supported by the Ludwig Foundation (K.C.G. and C.J.K.); the Mathers Fund (K.C.G.); the Howard Hughes Medical Institute (HHMI) (K.C.G. and R.N.); NIH grants U01DK085527 , U19AI116484 , R01NS100904 , and U01CA217851 (C.J.K.); and NIH grant 1R01DK115728 (C.J.K. and K.C.G.). P.D. is a Mark Foundation Momentum Fellow supported by the Mark Foundation for Cancer Research . Publisher Copyright: © 2020 Elsevier Inc. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
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