Single-cell transcriptomics identifies a WNT7A-FZD5 signaling axis that maintains fallopian tube stem cells in patient-derived organoids

Abdulkhaliq Alsaadi; Mara Artibani; Zhiyuan Hu; Nina Wietek; Matteo Morotti; Laura Santana Gonzalez; Moiad Alazzam; Jason Jiang; Beena Abdul; Hooman Soleymani majd; Levi L. Blazer; Jarret Adams; Francesca Silvestri; Sachdev S. Sidhu; Joan S. Brugge; Ahmed Ashour Ahmed

Cell Reports (Nov 2023)

Single-cell transcriptomics identifies a WNT7A-FZD5 signaling axis that maintains fallopian tube stem cells in patient-derived organoids

Abdulkhaliq Alsaadi,
Mara Artibani,
Zhiyuan Hu,
Nina Wietek,
Matteo Morotti,
Laura Santana Gonzalez,
Moiad Alazzam,
Jason Jiang,
Beena Abdul,
Hooman Soleymani majd,
Levi L. Blazer,
Jarret Adams,
Francesca Silvestri,
Sachdev S. Sidhu,
Joan S. Brugge,
Ahmed Ashour Ahmed

Affiliations

Abdulkhaliq Alsaadi: Ovarian Cancer Cell Laboratory, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK; Nuffield Department of Women’s & Reproductive Health, University of Oxford, Oxford OX3 9DU, UK
Mara Artibani: Ovarian Cancer Cell Laboratory, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK; Nuffield Department of Women’s & Reproductive Health, University of Oxford, Oxford OX3 9DU, UK; Gene Regulatory Networks in Development and Disease Laboratory, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK
Zhiyuan Hu: Ovarian Cancer Cell Laboratory, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK; Nuffield Department of Women’s & Reproductive Health, University of Oxford, Oxford OX3 9DU, UK; Gene Regulatory Networks in Development and Disease Laboratory, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK
Nina Wietek: Ovarian Cancer Cell Laboratory, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK; Nuffield Department of Women’s & Reproductive Health, University of Oxford, Oxford OX3 9DU, UK; Department of Gynecological Oncology, Churchill Hospital, Oxford University Hospitals, Oxford OX3 7LE, UK
Matteo Morotti: Ovarian Cancer Cell Laboratory, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK; Nuffield Department of Women’s & Reproductive Health, University of Oxford, Oxford OX3 9DU, UK; Department of Gynecological Oncology, Churchill Hospital, Oxford University Hospitals, Oxford OX3 7LE, UK
Laura Santana Gonzalez: Ovarian Cancer Cell Laboratory, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK; Nuffield Department of Women’s & Reproductive Health, University of Oxford, Oxford OX3 9DU, UK
Moiad Alazzam: Department of Gynecological Oncology, Churchill Hospital, Oxford University Hospitals, Oxford OX3 7LE, UK
Jason Jiang: Department of Gynecological Oncology, Churchill Hospital, Oxford University Hospitals, Oxford OX3 7LE, UK
Beena Abdul: Department of Gynecological Oncology, Churchill Hospital, Oxford University Hospitals, Oxford OX3 7LE, UK
Hooman Soleymani majd: Medical Sciences Division, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK
Levi L. Blazer: School of Pharmacy, University of Waterloo, Waterloo, ON, Canada
Jarret Adams: School of Pharmacy, University of Waterloo, Waterloo, ON, Canada
Francesca Silvestri: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
Sachdev S. Sidhu: School of Pharmacy, University of Waterloo, Waterloo, ON, Canada
Joan S. Brugge: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Boston, MA, USA
Ahmed Ashour Ahmed: Ovarian Cancer Cell Laboratory, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK; Nuffield Department of Women’s & Reproductive Health, University of Oxford, Oxford OX3 9DU, UK; Department of Gynecological Oncology, Churchill Hospital, Oxford University Hospitals, Oxford OX3 7LE, UK; Corresponding author

Journal volume & issue: Vol. 42, no. 11
p. 113354

Abstract

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Summary: The study of fallopian tube (FT) function in health and disease has been hampered by limited knowledge of FT stem cells and lack of in vitro models of stem cell renewal and differentiation. Using optimized organoid culture conditions to address these limitations, we find that FT stem cell renewal is highly dependent on WNT/β-catenin signaling and engineer endogenous WNT/β-catenin signaling reporter organoids to biomark, isolate, and characterize these cells. Using functional approaches, as well as bulk and single-cell transcriptomics analyses, we show that an endogenous hormonally regulated WNT7A-FZD5 signaling axis is critical for stem cell renewal and that WNT/β-catenin pathway-activated cells form a distinct transcriptomic cluster of FT cells enriched in extracellular matrix (ECM) remodeling and integrin signaling pathways. Overall, we provide a deep characterization of FT stem cells and their molecular requirements for self-renewal, paving the way for mechanistic work investigating the role of stem cells in FT health and disease.

CP: Stem cell research

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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