Next-Generation Surrogate Wnts Support Organoid Growth and Deconvolute Frizzled Pleiotropy In Vivo
| Autor: | Sanne de Haan, Kathrin Rösch, Roeland Nusse, Cayetano Pleguezuelos-Manzano, Jeroen P. Roose, Carol Piani, Kanako Yuki, Calvin J. Kuo, David Baker, Jacob Piehler, Changjiang You, António J. M. Santos, Jens Puschhof, Wieger Hemrika, Jarno Drost, Sylvia F. Boj, Hans Clevers, K. Christopher Garcia, Oghenekevwe M. Gbenedio, Melanie Ott, Ramazan Senlice, Wim de Lau, Jenny Yuan, Mario Vallon, Philippe Depeille, Weng Chuan Peng, Sean M. Wu, Claudia Y. Janda, Maarten H. Geurts, Andrew C.T. Ha, Luke T. Dang, Jan W. Buikema, Yi Miao |
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| Přispěvatelé: | Hubrecht Institute for Developmental Biology and Stem Cell Research |
| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
Frizzled Stem Cells Wnt signaling pathway LRP6 Cell Biology Biology Regenerative medicine Frizzled Receptors Article Cell biology Organoids 03 medical and health sciences 0302 clinical medicine Genetics Organoid Hepatocytes Molecular Medicine Stem cell Receptor Wnt Signaling Pathway 030217 neurology & neurosurgery WNT3A 030304 developmental biology |
| Zdroj: | Cell Stem Cell Cell Stem Cell, 27(5), 840-851.e6. Cell Press |
| ISSN: | 1875-9777 1934-5909 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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