Survival and function of mesenchymal stem cells (MSCs) depend on glucose to overcome exposure to long-term, severe and continuous hypoxia

Abstract

Use of mesenchymal stem cells (MSCs) has emerged as a potential new treatment for various diseases but has generated marginally successful results. A consistent finding of most studies is massive death of transplanted cells. The present study examined the respective roles of glucose and continuous severe hypoxia on MSC viability and function with respect to bone tissue engineering. We hereby demonstrate for the first time that MSCs survive exposure to long-term (12 days), severe (pO2 < 1.5 mmHg) hypoxia, provided glucose is available. To this end, an in vitro model that mimics the hypoxic environment and cell-driven metabolic changes encountered by grafted sheep cells was established. In this model, the hallmarks of hypoxia (low pO2, hypoxia inducible factor-1α expression and anaerobic metabolism) were present. When conditions switched from hypoxic (low pO2) to ischemic (low pO2 and glucose depletion), MSCs exhibited shrinking, decreased cell viability and ATP content due to complete exhaustion of glucose at day 6; these results provided evidence that ischemia led to the observed massive cell death. Moreover, MSCs exposed to severe, continuous hypoxia, but without any glucose shortage, remained viable and maintained both their in vitro proliferative ability after simulation with blood reperfusion at day 12 and their in vivo osteogenic ability. These findings challenge the traditional view according to which severe hypoxia per se is responsible for the massive MSC death observed upon transplantation of these cells and provide evidence that MSCs are able to withstand exposure to severe, continuous hypoxia provided that a glucose supply is available.

Hypoxia Inhibits De Novo Vascular Assembly of Adipose-Derived Stromal/Stem Cell Populations, but Promotes Growth of Preformed Vessels

“…Similar hypoxic resiliency and metabolic shifts have been demonstrated in ASCs 26 and other cell types. 27,28 This finding is promising regarding the ability of ASCs to endure harsh ischemic environments after transplantation.…”

The Matrikine Tenascin-C Protects Multipotential Stromal Cells/Mesenchymal Stem Cells from Death Cytokines Such as FasL

“…3 The loss in the implanted MSC numbers has been reported for implantation of several tissues using different implantation methods, including injection into the inflammatory bowel 4 and the infarcted hearts, 5,6 or implantation into the injured bone 7 and the ischemic kidney. 8 The disappearance of MSCs is closely associated with death-inducing conditions such as increased reactive oxygen species, 9 hypoxia, 10 and nutrient deprivation 11 in the wound environment along with nonspecific inflammation generated in response to implantation of any foreign material into the body.…”

Cell Sources for Bone Tissue Engineering: Insights from Basic Science

“…Following transplantation, cells are exposed to hypoxia until the construct can be properly vascularized by the host; therefore, methods to protect cells from apoptosis are essential. 106,107 Preconditioning in bioreactors may reinforce cell integration within artificial scaffolds before transplantation. 108,109 Predifferentiation in the osteogenic pathway can also be employed, but it decreases the capacity for expansion.…”