Myc Supports Self-Renewal of Basal Cells in the Esophageal Epithelium.

Tomoaki Hishida,Juan Carlos Izpisua Belmonte,Kei Yoshida,Estrella Nuñez Delicado,Sanjeeb Kumar Sahu,Yuta Takahashi,Antoni Castells,Javier Prieto,Ryuji Kato,Hiroshi Nakagawa,Yuto Takemoto,Paul S Knoepfler,Yuriko Hishida-Nozaki,Josep M Campistol,Eric Vazquez-Ferrer,Concepcion Rodriguez Esteban,Fumiyuki Hatanaka,Pradeep Reddy,David D O’Keefe

doi:10.3389/fcell.2022.786031

Abstract

It is widely believed that cellular senescence plays a critical role in both aging and cancer, and that senescence is a fundamental, permanent growth arrest that somatic cells cannot avoid. Here we show that Myc plays an important role in self-renewal of esophageal epithelial cells, contributing to their resistance to cellular senescence. Myc is homogeneously expressed in basal cells of the esophageal epithelium and Myc positively regulates their self-renewal by maintaining their undifferentiated state. Indeed, Myc knockout induced a loss of the undifferentiated state of esophageal epithelial cells resulting in cellular senescence while forced MYC expression promoted oncogenic cell proliferation. A superoxide scavenger counteracted Myc knockout-induced senescence, therefore suggesting that a mitochondrial superoxide takes part in inducing senescence. Taken together, these analyses reveal extremely low levels of cellular senescence and senescence-associated phenotypes in the esophageal epithelium, as well as a critical role for Myc in self-renewal of basal cells in this organ. This provides new avenues for studying and understanding the links between stemness and resistance to cellular senescence.

Highlights

Most cells do not proliferate indefinitely, but instead enter cellular senescence, a permanent cell cycle arrest triggered by excessive rounds of cell division, oncogenic stimuli, or genotoxic stresses (Kuilman et al, 2010)
It was suggested that MYC is necessary for proliferating cells to keep an undifferentiated state and maintain a low level of mitochondrial superoxide. These data revealed an essential role of MYC on the stemness of esophageal epithelial cells, which are highly resistant to senescence
This suggests that esophageal epithelial cells robustly proliferate and survive long enough to accumulate many somatic mutations without cellular senescence (Martincorena et al, 2018; Yokoyama et al, 2019)

Summary

INTRODUCTION

Most cells do not proliferate indefinitely, but instead enter cellular senescence, a permanent cell cycle arrest triggered by excessive rounds of cell division, oncogenic stimuli, or genotoxic stresses (Kuilman et al, 2010). Some cell types, such as adult/tissue stem cells and progenitors, show resistance to senescence. Forced-expression of MYC induced oncogenic cell proliferation while MYC knockout reduced the self-renewal capacity of esophageal epithelial cells, which resulted in cellular senescence, indicating the importance of MYC in preserving their self-renewal. It was suggested that MYC is necessary for proliferating cells to keep an undifferentiated state and maintain a low level of mitochondrial superoxide. Taken together, these data revealed an essential role of MYC on the stemness of esophageal epithelial cells, which are highly resistant to senescence

MATERIALS AND METHODS

A Lack of Senescence in the Esophagus

ETHICS STATEMENT