Next-Generation Surrogate Wnts Support Organoid Growth and Deconvolute Frizzled Pleiotropy In Vivo

Yi Miao, Andrew Ha, Wim de Lau, Kanako Yuki, António J M Santos, Changjiang You, Maarten H Geurts, Jens Puschhof, Cayetano Pleguezuelos-Manzano, Weng Chuan Peng, Ramazan Senlice, Carol Piani, Jan W Buikema, Oghenekevwe M Gbenedio, Mario Vallon, Jenny Yuan, Sanne de Haan, Wieger Hemrika, Kathrin Rösch, Luke T DangDavid Baker, Melanie Ott, Philippe Depeille, Sean M Wu, Jarno Drost, Roeland Nusse, Jeroen P Roose, Jacob Piehler, Sylvia F Boj, Claudia Y Janda, Hans Clevers, Calvin J Kuo, K Christopher Garcia

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

73 Citaten (Scopus)


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.

Originele taal-2Engels
Pagina's (van-tot)840-851.e6
TijdschriftCell stem cell
Nummer van het tijdschrift5
StatusGepubliceerd - 5 nov. 2020


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