Hypoxic preconditioning enhances the therapeutic potential of the secretome from cultured human mesenchymal stem cells in experimental traumatic brain injury

Abstract

Bone-marrow-derived human MSCs (mesenchymal stem cells) support repair when administered to animals with TBI (traumatic brain injury) in large part through secreted trophic factors. We directly tested the ability of the culture medium (or secretome) collected from human MSCs under normoxic or hypoxic conditions to protect neurons in a rat model of TBI. Concentrated conditioned medium from cultured human MSCs or control medium was infused through the tail vein of rats subjected to TBI. We have demonstrated that MSCs cultured in hypoxia were superior to those cultured in normoxia in inducing expression of both HGF (hepatocyte growth factor) and VEGF (vascular endothelial growth factor) in the cultured medium. We showed further that rats treated with the secretome from both normoxic- and hypoxic-preconditioned MSCs performed significantly better than the controls in both motor and cognitive functional test. Subsequent post-mortem evaluation of brain damage at the 4-day time point confirmed that both normoxic- and hypoxic-preconditioned MSC secretome-treated rats had significantly greater numbers of newly forming neurons, but significantly less than the controls in brain damaged volume and apoptosis. The TBI rats treated with hypoxic-preconditioned MSC secretome performed significantly better in both motor and cognitive function tests and neurogenesis, and had significantly less brain damage than the TBI rats treated with the normoxic-preconditioned MSC secretome. Collectively, these findings suggest that MSCs secrete bioactive factors, including HGF and VEGF, that stimulate neurogenesis and improve outcomes of TBI in a rat model. Hypoxic preconditioning enhances the secretion of these bioactive factors from the MSCs and the therapeutic potential of the cultured MSC secretome in experimental TBI.

Activity of mesenchymal stem cells in therapies for chronic skin wound healing

“…103 Conversely, Chang et al recently demonstrated the advantages of preconditioning MSCs in hypoxia, which was shown to improve the secretory capabilities of the cells (VEGF, HGF, and others), a main benefit of MSC therapy. 104 Gene therapy in MSCs has also received some attention, as Wang et al recently showed that adenoviral upregulation of protein kinase G1α improved MSC survival following implantation into a similar cardiac infarct model. 101 Additional recent studies have examined the possibility of exploiting endogenous signaling pathways in promoting MSC survival in a variety of wound healing contexts.…”

Increased leptin by hypoxic-preconditioning promotes autophagy of mesenchymal stem cells and protects them from apoptosis

“…Sci China Life Sci, 2014Sci, , 57: 171 -180, doi: 10.1007 Although severe hypoxia can lead to cell death for certain cell types such as endothelial cells, repeated episodes of short periods' exposure to hypoxia (hypoxic-preconditioning) have shown conferring cytoprotective benefits. Research done in our laboratory and others has revealed that hypoxic-preconditioning protects bone marrow-derived mesenchymal stem cells (MSCs) from apoptosis and enhances cell survival after implantation [1,2]. However, the mechanisms underlying the beneficial effects of hypoxia preconditioned MSCs remain unclear.…”

“…Research done in our laboratory and others has revealed that hypoxic-preconditioning protects bone marrow-derived mesenchymal stem cells (MSCs) from apoptosis and enhances cell survival after implantation [1,2]. However, the mechanisms underlying the beneficial effects of hypoxia preconditioned MSCs remain unclear.…”

Hypoxic Preconditioning Increases the Neuroprotective Effects of Mesenchymal Stem Cells in a Rat Model of Spinal Cord Injury

“…In addition, VEGF has neurotrophic and neuroprotective effects in vitro and in vivo [23,24]. Although several studies have demonstrated that VEGF mRNA or protein expression is upregulated in hypoxia-preconditioned MSCs [25][26][27], few reports have demonstrated the neuroprotective effects of hypoxia-preconditioned MSCs transplantation to treat SCI. Therefore, the present study aimed to determine whether hypoxia-preconditioned MSCs have a neuroprotective effect in vitro and in vivo and improve functional defects in a rat model of SCI.…”