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

doi:10.1016/j.celrep.2023.113354

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

Cell Rep. 2023 Nov 28;42(11):113354. doi: 10.1016/j.celrep.2023.113354. Epub 2023 Nov 1.

Authors

Abdulkhaliq Alsaadi¹, Mara Artibani², Zhiyuan Hu², Nina Wietek³, Matteo Morotti³, Laura Santana Gonzalez¹, Moiad Alazzam⁴, Jason Jiang⁴, Beena Abdul⁴, Hooman Soleymani Majd⁵, Levi L Blazer⁶, Jarret Adams⁶, Francesca Silvestri⁷, Sachdev S Sidhu⁶, Joan S Brugge⁸, Ahmed Ashour Ahmed⁹

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Department of Gynecological Oncology, Churchill Hospital, Oxford University Hospitals, Oxford OX3 7LE, UK.
⁵ Medical Sciences Division, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
⁶ School of Pharmacy, University of Waterloo, Waterloo, ON, Canada.
⁷ Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
⁸ Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Boston, MA, USA.
⁹ 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. Electronic address: ahmed.ahmed@wrh.ox.ac.uk.

PMID: 37917586
DOI: 10.1016/j.celrep.2023.113354

Abstract

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.

Keywords: CP: Stem cell research; ECM; WNT; estrogen; fallopian tube; organoids; ovarian cancer; single-cell RNA sequencing; stem cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Fallopian Tubes* / metabolism
Female
Frizzled Receptors / metabolism
Humans
Organoids / metabolism
Stem Cells / metabolism
Transcriptome / genetics
Wnt Proteins / genetics
Wnt Proteins / metabolism
Wnt Signaling Pathway
beta Catenin* / metabolism

Substances

beta Catenin
WNT7A protein, human
Wnt Proteins
FZD5 protein, human
Frizzled Receptors