Directed Differentiation of Human Induced Pluripotent Stem Cells into Fallopian Tube Epithelium

Nur Yucer; Marie Holzapfel; Tilley Jenkins Vogel; Lindsay Lenaeus; Loren Ornelas; Anna Laury; Dhruv Sareen; Robert Barrett; Beth Y. Karlan; Clive N. Svendsen

doi:10.1038/s41598-017-05519-2

Directed Differentiation of Human Induced Pluripotent Stem Cells into Fallopian Tube Epithelium

Nur Yucer, Marie Holzapfel, Tilley Jenkins Vogel, Lindsay Lenaeus, Loren Ornelas, Anna Laury, Dhruv Sareen, Robert Barrett, Beth Y. Karlan, Clive N. Svendsen

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

62 Scopus citations

Abstract

The fallopian tube epithelium (FTE) has been recognized as a site of origin of high-grade serous ovarian cancer (HGSC). However, the absence of relevant in vitro human models that can recapitulate tissue-specific architecture has hindered our understanding of FTE transformation and initiation of HGSC. Here, induced pluripotent stem cells (iPSCs) were used to establish a novel 3-dimensional (3D) human FTE organoid in vitro model containing the relevant cell types of the human fallopian tube as well as a luminal architecture that closely reflects the organization of fallopian tissues in vivo. Modulation of Wnt and BMP signaling directed iPSC differentiation into Müllerian cells and subsequent use of pro-Müllerian growth factors promoted FTE precursors. The expression and localization of Müllerian markers verified correct cellular differentiation. An innovative 3D growth platform, which enabled the FTE organoid to self-organize into a convoluted luminal structure, permitted matured differentiation to a FTE lineage. This powerful human-derived FTE organoid model can be used to study the earliest stages of HGSC development and to identify novel and specific biomarkers of early fallopian tube epithelial cell transformation.

Original language	English (US)
Article number	10741
Journal	Scientific reports
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/s41598-017-05519-2
State	Published - Dec 1 2017
Externally published	Yes

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title = "Directed Differentiation of Human Induced Pluripotent Stem Cells into Fallopian Tube Epithelium",

abstract = "The fallopian tube epithelium (FTE) has been recognized as a site of origin of high-grade serous ovarian cancer (HGSC). However, the absence of relevant in vitro human models that can recapitulate tissue-specific architecture has hindered our understanding of FTE transformation and initiation of HGSC. Here, induced pluripotent stem cells (iPSCs) were used to establish a novel 3-dimensional (3D) human FTE organoid in vitro model containing the relevant cell types of the human fallopian tube as well as a luminal architecture that closely reflects the organization of fallopian tissues in vivo. Modulation of Wnt and BMP signaling directed iPSC differentiation into M{\"u}llerian cells and subsequent use of pro-M{\"u}llerian growth factors promoted FTE precursors. The expression and localization of M{\"u}llerian markers verified correct cellular differentiation. An innovative 3D growth platform, which enabled the FTE organoid to self-organize into a convoluted luminal structure, permitted matured differentiation to a FTE lineage. This powerful human-derived FTE organoid model can be used to study the earliest stages of HGSC development and to identify novel and specific biomarkers of early fallopian tube epithelial cell transformation.",

author = "Nur Yucer and Marie Holzapfel and \{Jenkins Vogel\}, Tilley and Lindsay Lenaeus and Loren Ornelas and Anna Laury and Dhruv Sareen and Robert Barrett and Karlan, \{Beth Y.\} and Svendsen, \{Clive N.\}",

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year = "2017",

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doi = "10.1038/s41598-017-05519-2",

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AU - Yucer, Nur

AU - Holzapfel, Marie

AU - Jenkins Vogel, Tilley

AU - Lenaeus, Lindsay

AU - Ornelas, Loren

AU - Laury, Anna

AU - Sareen, Dhruv

AU - Barrett, Robert

AU - Karlan, Beth Y.

AU - Svendsen, Clive N.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - The fallopian tube epithelium (FTE) has been recognized as a site of origin of high-grade serous ovarian cancer (HGSC). However, the absence of relevant in vitro human models that can recapitulate tissue-specific architecture has hindered our understanding of FTE transformation and initiation of HGSC. Here, induced pluripotent stem cells (iPSCs) were used to establish a novel 3-dimensional (3D) human FTE organoid in vitro model containing the relevant cell types of the human fallopian tube as well as a luminal architecture that closely reflects the organization of fallopian tissues in vivo. Modulation of Wnt and BMP signaling directed iPSC differentiation into Müllerian cells and subsequent use of pro-Müllerian growth factors promoted FTE precursors. The expression and localization of Müllerian markers verified correct cellular differentiation. An innovative 3D growth platform, which enabled the FTE organoid to self-organize into a convoluted luminal structure, permitted matured differentiation to a FTE lineage. This powerful human-derived FTE organoid model can be used to study the earliest stages of HGSC development and to identify novel and specific biomarkers of early fallopian tube epithelial cell transformation.

AB - The fallopian tube epithelium (FTE) has been recognized as a site of origin of high-grade serous ovarian cancer (HGSC). However, the absence of relevant in vitro human models that can recapitulate tissue-specific architecture has hindered our understanding of FTE transformation and initiation of HGSC. Here, induced pluripotent stem cells (iPSCs) were used to establish a novel 3-dimensional (3D) human FTE organoid in vitro model containing the relevant cell types of the human fallopian tube as well as a luminal architecture that closely reflects the organization of fallopian tissues in vivo. Modulation of Wnt and BMP signaling directed iPSC differentiation into Müllerian cells and subsequent use of pro-Müllerian growth factors promoted FTE precursors. The expression and localization of Müllerian markers verified correct cellular differentiation. An innovative 3D growth platform, which enabled the FTE organoid to self-organize into a convoluted luminal structure, permitted matured differentiation to a FTE lineage. This powerful human-derived FTE organoid model can be used to study the earliest stages of HGSC development and to identify novel and specific biomarkers of early fallopian tube epithelial cell transformation.

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Directed Differentiation of Human Induced Pluripotent Stem Cells into Fallopian Tube Epithelium

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