Heat Shock Alters Mesenchymal Stem Cell Identity and Induces Premature Senescence.

Chen Shimoni,Iftach Schauten,Dana Nir,Carmit Strauss,Ivana Ribarski-Chorev,Sharon Schlesinger,Myah Goldstein

doi:10.3389/fcell.2020.565970

Chen Shimoni, Iftach Schauten + Show 5 more

Open Access

https://doi.org/10.3389/fcell.2020.565970

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Abstract

Heat stress can have a serious impact on the health of both humans and animals. A major question is how heat stress affects normal development and differentiation at both the cellular and the organism levels. Here we use an in vitro experimental system to address how heat shock treatment influences the properties of bovine mesenchymal stem cells (MSCs)—multipotent progenitor cells—which are found in most tissues. Because cattle are sensitive to harsh external temperatures, studying the effects of heat shock on MSCs provides a unique platform to address cellular stress in a physiologically relevant model organism. Following isolation and characterization of MSCs from the cow’s umbilical cord, heat shock was induced either as a pulse (1 h) or continuously (3 days), and consequent effects on MSCs were characterized. Heat shock induced extensive phenotypic changes in MSCs and dramatically curtailed their capacity to proliferate and differentiate. These changes were associated with a partial arrest in the G1/S or G2/M checkpoints. Furthermore, MSCs lost their ability to resolve the inflammatory response of RAW macrophages in coculture. A possible explanation for this loss of function is the accumulation of reactive oxygen species and malfunction of the mitochondria in the treated cells. Heat shock treatments resulted in stress-induced premature senescence, affecting the MSCs’ ability to proliferate properly for many cell passages to follow. Exposure to elevated external temperatures leads to mitochondrial damage and oxidative stress, which in turn conveys critical changes in the proliferation, differentiation, and immunomodulatory phenotype of heat-stressed MSCs. A better understanding of the effect of heat shock on humans and animals may result in important health and economic benefits.

Highlights

Elevated ambient temperatures are increasing in frequency and can severely affect human and farm animal well-being, especially during the summer period
Bovine umbilical cord-Mesenchymal stem cells were isolated from bovine umbilical cord (bUC) as described in “Materials and Methods” and cultivated for 15 cell passages
PBMCs were isolated from whole blood and cocultured with bUC-mesenchymal stem cells (MSCs) for 4 days at a ratio of 1:5, respectively, with or without activation with concanavalin A (Con-A)

Summary

Introduction

Elevated ambient temperatures are increasing in frequency and can severely affect human and farm animal well-being, especially during the summer period. Heat stress increases the concentration of intracellular reactive oxygen species (ROS) in cells (Slimen et al, 2014) and has detrimental effects on mammalian fertility and well-being (Kitagawa et al, 2004; Agarwal et al, 2014). Increased ROS levels elicit stem cell depletion and functional defects in several tissues (Burgess et al, 2014). The frequency of many chronic inflammation–related diseases is elevated during a hot period (Olde Riekerink et al, 2007; Chen S. et al, 2018), resulting in reduced animal welfare and significant economic losses to the dairy industry (Key et al, 2014). Heat is a common stressor, the functional connection between elevated temperatures and the higher rates of chronic inflammation is still obscure

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