Cited by 151Wnt/β-catenin signaling in development and cancerHedgehog Signaling Pathway StudiesPluripotent Stem Cells Research

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

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Miao, Yi, Ha, Andrew, de Lau, Wim, Yuki, Kanako, Santos, António J.M., You, Changjiang, Geurts, Maarten H., Puschhof, Jens +25 more·2020·Cell Stem Cell

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.

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Crossref · 10.1016/j.stem.2020.07.020

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  • Conditioned medium from engineered cell lines producing biologically active growth factors can replace commonly used growth factors such as Wnt3a ligands.

    “The use of conditioned medium from engineered cell lines producing biologically active growth factors, e.g., L Wnt-3A, can replace commonly used growth factors, such as Wnt3a ligands80.”

    From Organoids (2022) · cites this paper as [80]

  • Novel surrogate molecules are beginning to emerge as potential substitutes for conditioned medium.

    “Thus, novel sorrugate molecules are starting to arise as potential substitutes to condition medium80,81.”

    From Organoids (2022) · cites this paper as [80]

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Authors
Miao, Y., Ha, A., de Lau, W., Yuki, K., Santos, A. J. M., You, C., Geurts, M. H., Puschhof, J., Pleguezuelos-Manzano, C., Peng, W. C., Senlice, R., Piani, C., Buikema, J. W., Gbenedio, O. M., Vallon, M., Yuan, J., de Haan, S., Hemrika, W., Rösch, K., Dang, L. T., Baker, D., Ott, M., Depeille, P., Wu, S. M., Drost, J., Nusse, R., Roose, J. P., Piehler, J., Boj, S. F., Janda, C. Y., Clevers, H., Kuo, C. J., & Garcia, K. C.
Affiliations
  • Howard Hughes Medical Institute (US)
  • Stanford Medicine (US)
  • Osnabrück University (DE)
  • University Medical Center Utrecht (NL)
  • Utrecht University (NL)
  • University of California, San Francisco (US)
  • Gladstone Institutes (US)
  • Oncode Institute (NL)
  • Princess Máxima Center (NL)
Venue
Cell Stem Cell
Publisher
Elsevier BV
Published
2020-11
Volume
27
Issue
5
Pages
840-851.e6
ISSN
  • 1875-9777 (ISSN-L)
  • 1934-5909
OpenAlex
W3061588182
Cited by
151
References
57
Citations by year
2026: 15 · 2025: 25 · 2024: 24 · 2023: 32 · 2022: 24 · 2021: 28 · 2020: 3
FWCI
7.06
Type
journal article
Language
en
Open access
Locations
  • Cell stem cell (publishedVersion)
  • PubMed (publishedVersion)
  • KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • HAL (submittedVersion, other-oa)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • Ludwig Institute for Cancer Research
  • G. Harold and Leila Y. Mathers Foundation
  • Mark Foundation For Cancer Research
  • National Institutes of Health
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
Keywords
Wnt signaling, Frizzled receptors, LRP6, organoid expansion, liver zonation, stem cell homeostasis, regenerative medicine, kidney organoids, colon organoids, hepatocyte organoids
MeSH terms
Organoids, Stem Cells, Hepatocytes, Frizzled Receptors, Wnt Signaling Pathway

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