SMAD2/3 Signaling in the Uterine Epithelium Controls Endometrial Cell Homeostasis and Regeneration

Authors

Maya L Kriseman
Suni Tang
Zian Liao
Peixin Jiang
Sydney E Parks
Dominique I Cope
Fei Yuan
Fengju Chen
Ramya P Masand
Patricia D Castro
Michael M Ittmann
Chad J Creighton
Zhi Tan
Diana Monsivais

Publication Date

3-11-2023

Journal

Communications Biology

DOI

10.1038/s42003-023-04619-2

PMID

36906706

PMCID

PMC10008566

PubMedCentral® Posted Date

3-11-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Female, Mice, Cell Differentiation, Endometrium, Epithelium, Homeostasis, Uterus, Smad Proteins, Self-renewal, Stem-cell niche

Abstract

The regenerative potential of the endometrium is attributed to endometrial stem cells; however, the signaling pathways controlling its regenerative potential remain obscure. In this study, genetic mouse models and endometrial organoids are used to demonstrate that SMAD2/3 signaling controls endometrial regeneration and differentiation. Mice with conditional deletion of SMAD2/3 in the uterine epithelium using Lactoferrin-iCre develop endometrial hyperplasia at 12-weeks and metastatic uterine tumors by 9-months of age. Mechanistic studies in endometrial organoids determine that genetic or pharmacological inhibition of SMAD2/3 signaling disrupts organoid morphology, increases the glandular and secretory cell markers, FOXA2 and MUC1, and alters the genome-wide distribution of SMAD4. Transcriptomic profiling of the organoids reveals elevated pathways involved in stem cell regeneration and differentiation such as the bone morphogenetic protein (BMP) and retinoic acid signaling (RA) pathways. Therefore, TGFβ family signaling via SMAD2/3 controls signaling networks which are integral for endometrial cell regeneration and differentiation.

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