Beclin-1-Dependent Autophagy, but Not Apoptosis, Is Critical for Stem-Cell-Mediated Endometrial Programming and the Establishment of Pregnancy

Authors

Pooja Popli
Suni Tang
Sangappa B Chadchan
Chandni Talwar
Edmund B Rucker
Xiaoming Guan
Diana Monsivais
John P Lydon
Christina L Stallings
Kelle H Moley
Ramakrishna Kommagani

Publication Date

5-22-2023

Journal

Developmental Cell

DOI

10.1016/j.devcel.2023.03.013

PMID

37040770

PMCID

PMC10289806

PubMedCentral® Posted Date

5-22-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Animals, Female, Humans, Mice, Pregnancy, Autophagy, Beclin-1, Endometrium, Stem Cells, Uterus, endometrium, beclin-1, stem cells, morphogenesis

Abstract

The human endometrium shows a remarkable regenerative capacity that enables cyclical regeneration and remodeling throughout a woman's reproductive life. Although early postnatal uterine developmental cues direct this regeneration, the vital factors that govern early endometrial programming are largely unknown. We report that Beclin-1, an essential autophagy-associated protein, plays an integral role in uterine morphogenesis during the early postnatal period. We show that conditional depletion of Beclin-1 in the uterus triggers apoptosis and causes progressive loss of Lgr5+/Aldh1a1+ endometrial progenitor stem cells, with concomitant loss of Wnt signaling, which is crucial for stem cell renewal and epithelial gland development. Beclin-1 knockin (Becn1 KI) mice with disabled apoptosis exhibit normal uterine development. Importantly, the restoration of Beclin-1-driven autophagy, but not apoptosis, promotes normal uterine adenogenesis and morphogenesis. Together, the data suggest that Beclin-1-mediated autophagy acts as a molecular switch that governs the early uterine morphogenetic program by maintaining the endometrial progenitor stem cells.