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.
Highlights
Fallopian tube epithelium is composed of a polarized columnar epithelium including ciliated and secretory cells
Reprogramming to human induced pluripotent stem cells (iPSCs) possesses the essential advantages of eliminating the requirement for embryonic material while allowing for the generation of pluripotent cells with known genetic factors in a patient-specific manner
Priming the intermediate mesoderm (IM) into only the desired cell fate has been a challenge for the iPSC-derived organoid model
Summary
Fallopian tube epithelium is composed of a polarized columnar epithelium including ciliated and secretory cells. It has been challenging to engineer silent and expressed mutations with the correct expression timeframe as well as accurate targeting to specific tissue and cell types, such as the secretory cell of the fallopian tube. Patient-derived iPSCs have been used to model several inherited human diseases and to successfully generate relevant cell types that display disease pathogenesis[17,18,19,20]. Remaining challenges with iPSC-based modeling include establishing direct differentiation protocols for desired cell types and integrating the differentiated cells into functional tissue structures. We describe a rapid and efficient method to create an iPSC-derived 3D model of human FTE with the desired cell types and luminal architecture. Staining of secretory and ciliated cellular components demonstrated that these structures accurately model fallopian tube architecture
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