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.

Keywords: O2 tension; hypoxia; hypoxia in vitro models; hypoxia inducible factors; intracellular signaling; metabolism; stemness.

Figure 1

Different O₂ partial pressure in body districts.

Figure 2

Scheme of HIF-1α activation during different O₂ level exposure. Under normoxia condition (≅21% O₂) HIF is rapidly degraded by proteasomal machinery. During hypoxia (≤10% O₂) HIF is stabilized and translocated into the nucleus where heterodimerized with HIF-1β. Heterodimer HIF-1α/β, regulates HRE target genes (some of which are indicated) involved in different biological responses.

Figure 3

Schematic representation of methodology for data research and analysis performed with specific keywords in Scopus Database related to the link between hypoxia and stemness preservation elaborated in this review.

Figure 4

Parameters and outcomes for in vitro hypoxia exploitations. Different hypoxic stimuli, cells sources, biological responses, and pathways principally discussed in the review.

Figure 5

Most relevant Systems used to induce in vitro physical hypoxia. Gas mixture from a single tank can be connected directly to (A) hypoxic chambers before their incubation in standard CO₂ incubator or (B) incubator. A similar mechanism is used for (C) AnaeroPack system. (D) “Tri-Gas” incubator: only two gases are supplied, CO₂, as usual, and N₂, that can be modulated to reduce O₂. (E) hypoxic workstation. (F) example of microfluidic devices.

Figure 6

Summary of stem cell metabolic state during hypoxia condition and molecular pathways linking HIF-stemness genes-metabolism switch to glycolysis.