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

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

99 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 - 05 Nov 2020

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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

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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.",

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year = "2020",

month = nov,

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

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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

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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.

U2 - 10.1016/j.stem.2020.07.020

DO - 10.1016/j.stem.2020.07.020

M3 - Article

C2 - 32818433

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

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