Insight into Hypoxia Stemness Control

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.

Hypoxia-Mimetic CoCl2 Agent Enhances Pro-Angiogenic Activities in Ovine Amniotic Epithelial Cells-Derived Conditioned Medium

“…Even if several pieces of evidence converge in demonstrating that in vitro parameters can influence stem cell properties [50], the current stem cell expansion protocols are frequently set up without considering the native environmental conditions. An underestimated cultural parameter is the oxygen tension that in the majority of stem cell amplification protocols is maintained at air tension levels because it is forgotten that, instead, the natural niche stem cell environment recognizes physiologically low O2 tension in several districts [28].…”

“…Consistent literature demonstrates a positive correlation existing between low O2 environment and stemness retention [28], even if few data have been collected to date on AECs. In this context, previous works have reported that AECs under 20% O2 spontaneously reduce the pluripotent expression genes [10] and go into epithelial-to-mesenchymal transition (EMT) [31,32].…”

“…In these O2-controlled in vivo environments, stem cells may maintain a selective advantage suitable for their biological roles. Indeed, O2 availability, triggering specific intracellular signalling, can modulate gene expression, affecting cell fate [28]. Cellular adaptive responses to hypoxia are mainly mediated by the transcription factor hypoxia-inducible factor-1 (HIF-1), which induces transcriptional activation of various genes, promoting angiogenesis, cell self-renewal, and survival.…”

“…In cell cultures, hypoxic conditions can be induced by modulating O2 levels with a specific gas mixture linked to a hypoxic chamber or incubator or directly with a tri-gas incubator [28]. However, to avoid variability linked to low oxygen incubator use, an alternative approach is represented by chemical "hypoxic mimetic compounds" treatments.…”

Hydrogel, Electrospun and Composite Materials for Bone/Cartilage and Neural Tissue Engineering

“…MSCs in mild hypoxia show lower necrosis and cell injury, higher proliferation and preferential differentiation into osteocytes instead of adipocytes, but their metabolism is slowed down, and migration capability is affected [36]. A hypoxic microenvironment influences specific stem cells in different ways, and studies show ambiguous results but the majority agree that hypoxia plays a key role in maintaining stemness and affects differentiation phenotype [37,38].…”