Insight into Hypoxia Stemness Control.

Miriam Di Mattia,Enrico Dainese,Barbara Barboni,Annamaria Cimini,Beatrice Dufrusine,Paolo Berardinelli,Valentina Russo,Alessia Peserico,Maria Rita Citeroni,Annunziata Mauro

doi:10.3390/cells10082161

Abstract

Recently, the research on stemness and multilineage differentiation mechanisms has greatly increased its value due to the potential therapeutic impact of stem cell-based approaches. Stem cells modulate their self-renewing and differentiation capacities in response to endogenous and/or extrinsic factors that can control stem cell fate. One key factor controlling stem cell phenotype is oxygen (O2). Several pieces of evidence demonstrated that the complexity of reproducing O2 physiological tensions and gradients in culture is responsible for defective stem cell behavior in vitro and after transplantation. This evidence is still worsened by considering that stem cells are conventionally incubated under non-physiological air O2 tension (21%). Therefore, the study of mechanisms and signaling activated at lower O2 tension, such as those existing under native microenvironments (referred to as hypoxia), represent an effective strategy to define if O2 is essential in preserving naïve stemness potential as well as in modulating their differentiation. Starting from this premise, the goal of the present review is to report the status of the art about the link existing between hypoxia and stemness providing insight into the factors/molecules involved, to design targeted strategies that, recapitulating naïve O2 signals, enable towards the therapeutic use of stem cell for tissue engineering and regenerative medicine.

Highlights

IntroductionMolecular oxygen (O2 ) is necessary for animal life and is essential for a variety of biological processes involved in the survival of prokaryotic and eukaryotic cells
The present review aims to highlight the correlation existing between hypoxia and stemness focusing on cell culture models as invaluable research instruments for the comprehension of physiological hypoxia-induced mechanisms enabling the development of novel approaches to improve stem cell-based therapeutic strategies
The O2 tension, lowered to mimic niche microenvironment, has been successfully proposed to preserve cells phenotype during expansion for stem cell populations limited in supply

Summary

Introduction

Molecular oxygen (O2 ) is necessary for animal life and is essential for a variety of biological processes involved in the survival of prokaryotic and eukaryotic cells. O2 usage by cells is various, depending on the cell type and function. O2 uptake occurs by direct transport across the cell membrane and 90% of O2 is consumed by mitochondria during respiration and oxidative phosphorylation processes [1]. The citric acid cycle and β-oxidation of fatty acids are tightly associated with the process of ATP production. O2 availability is essential for cell functions, and decreased

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