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. Dang; David 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

doi:10.1016/j.stem.2020.07.020

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal Article › peer-review

111 Citations (Scopus)

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.

Original language	English
Pages (from-to)	840-851.e6
Journal	Cell Stem Cell
Volume	27
Issue number	5
DOIs	https://doi.org/10.1016/j.stem.2020.07.020
Publication status	Published - 5 Nov 2020
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2020 Elsevier Inc.

Keywords

DARPin
Frizzled
Wnt
canonical Wnt signaling
organoids
protein engineering
regenerative medicine
stem cell
surrogate Wnt

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10.1016/j.stem.2020.07.020

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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., ... Garcia, K. C. (2020). Next-Generation Surrogate Wnts Support Organoid Growth and Deconvolute Frizzled Pleiotropy In Vivo. Cell Stem Cell, 27(5), 840-851.e6. https://doi.org/10.1016/j.stem.2020.07.020

@article{e9067efe4b1546d08dbace7b98d8cb44,

title = "Next-Generation Surrogate Wnts Support Organoid Growth and Deconvolute Frizzled Pleiotropy In Vivo",

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.",

keywords = "DARPin, Frizzled, Wnt, canonical Wnt signaling, organoids, protein engineering, regenerative medicine, stem cell, surrogate Wnt",

author = "Yi Miao and Andrew Ha and \{de Lau\}, Wim and Kanako Yuki and Santos, \{Ant{\'o}nio J.M.\} and Changjiang You and Geurts, \{Maarten H.\} and Jens Puschhof and Cayetano Pleguezuelos-Manzano and Peng, \{Weng Chuan\} and Ramazan Senlice and Carol Piani and Buikema, \{Jan W.\} and Gbenedio, \{Oghenekevwe M.\} and Mario Vallon and Jenny Yuan and \{de Haan\}, Sanne and Wieger Hemrika and Kathrin R{\"o}sch and Dang, \{Luke T.\} and David Baker and Melanie Ott and Philippe Depeille and Wu, \{Sean M.\} and Jarno Drost and Roeland Nusse and Roose, \{Jeroen P.\} and Jacob Piehler and Boj, \{Sylvia F.\} and Janda, \{Claudia Y.\} and Hans Clevers and Kuo, \{Calvin J.\} and Garcia, \{K. Christopher\}",

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = nov,

day = "5",

doi = "10.1016/j.stem.2020.07.020",

language = "English",

volume = "27",

pages = "840--851.e6",

journal = "Cell Stem Cell",

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Miao, Y, Ha, A, de Lau, W, Yuki, K, Santos, AJM, You, C, Geurts, MH, Puschhof, J, Pleguezuelos-Manzano, C, Peng, WC, Senlice, R, Piani, C, Buikema, JW, Gbenedio, OM, Vallon, M, Yuan, J, de Haan, S, Hemrika, W, Rösch, K, Dang, LT, Baker, D, Ott, M, Depeille, P, Wu, SM, Drost, J, Nusse, R, Roose, JP, Piehler, J, Boj, SF, Janda, CY, Clevers, H, Kuo, CJ & Garcia, KC 2020, 'Next-Generation Surrogate Wnts Support Organoid Growth and Deconvolute Frizzled Pleiotropy In Vivo', Cell Stem Cell, vol. 27, no. 5, pp. 840-851.e6. https://doi.org/10.1016/j.stem.2020.07.020

TY - JOUR

T1 - Next-Generation Surrogate Wnts Support Organoid Growth and Deconvolute Frizzled Pleiotropy In Vivo

AU - Miao, Yi

AU - Ha, Andrew

AU - de Lau, Wim

AU - Yuki, Kanako

AU - Santos, António J.M.

AU - You, Changjiang

AU - Geurts, Maarten H.

AU - Puschhof, Jens

AU - Pleguezuelos-Manzano, Cayetano

AU - Peng, Weng Chuan

AU - Senlice, Ramazan

AU - Piani, Carol

AU - Buikema, Jan W.

AU - Gbenedio, Oghenekevwe M.

AU - Vallon, Mario

AU - Yuan, Jenny

AU - de Haan, Sanne

AU - Hemrika, Wieger

AU - Rösch, Kathrin

AU - Dang, Luke T.

AU - Baker, David

AU - Ott, Melanie

AU - Depeille, Philippe

AU - Wu, Sean M.

AU - Drost, Jarno

AU - Nusse, Roeland

AU - Roose, Jeroen P.

AU - Piehler, Jacob

AU - Boj, Sylvia F.

AU - Janda, Claudia Y.

AU - Clevers, Hans

AU - Kuo, Calvin J.

AU - Garcia, K. Christopher

PY - 2020/11/5

Y1 - 2020/11/5

N2 - 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.

AB - 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.

KW - DARPin

KW - Frizzled

KW - Wnt

KW - canonical Wnt signaling

KW - organoids

KW - protein engineering

KW - regenerative medicine

KW - stem cell

KW - surrogate Wnt

UR - https://www.webofscience.com/wos/woscc/full-record/WOS:000588320400014

UR - https://openalex.org/W3061588182

UR - https://www.scopus.com/pages/publications/85090222968

U2 - 10.1016/j.stem.2020.07.020

DO - 10.1016/j.stem.2020.07.020

M3 - Journal Article

SN - 1934-5909

VL - 27

SP - 840-851.e6

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 5

ER -

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

Abstract

Bibliographical note

Keywords

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