Hypoxic Preconditioning Augments the Therapeutic Efficacy of Bone Marrow Stromal Cells in a Rat Ischemic Stroke Model

Abstract

Transplantation of bone marrow stromal cells (BMSCs) is a promising therapy for ischemic stroke, but the poor oxygen environment in brain lesions limits the efficacy of cell-based therapies. Here, we tested whether hypoxic preconditioning (HP) could augment the efficacy of BMSC transplantation in a rat ischemic stroke model and investigated the underlying mechanism of the effect of HP. In vitro, BMSCs were divided into five passage (P0, P1, P2, P3, and P4) groups, and HP was applied to the groups by incubating the cells with 1% oxygen for 0, 4, 8, 12, and 24 h, respectively. We demonstrated that the expression of hypoxia-inducible factor-1α (HIF-1α) was increased in the HP-treated BMSCs, while their viability was unchanged. We also found that HP decreased the apoptosis of BMSCs during subsequent simulated ischemia-reperfusion (I/R) injury, especially in the 8-h HP group. In vivo, a rat transient focal cerebral ischemia model was established. These rats were administered normal cultured BMSCs (N-BMSCs), HP-treated BMSCs (H-BMSCs), or DMEM cell culture medium (control) at 24 h after the ischemic insult. Compared with the DMEM control group, the two BMSC-transplanted groups exhibited significantly improved functional recovery and reduced infarct volume, especially the H-BMSC group. Moreover, HP decreased neuronal apoptosis and enhanced the expression of BDNF and VEGF in the ischemic brain. Survival and differentiation of transplanted BMSCs were also increased by HP, and the quantity of engrafted BMSCs was significantly correlated with neurological function improvement. These results suggest that HP may enhance the therapeutic efficacy of BMSCs in an ischemic stroke model. The underlying mechanism likely involves the inhibition of caspase-3 activation and an increasing expression of HIF-1α, which promotes angiogenesis and neurogenesis and thereby reduces neuronal death and improves neurological function.

Hypoxic conditioned medium derived from bone marrow mesenchymal stromal cells protects against ischemic stroke in rats

“…Various pathological mechanisms are involved in the pathogenesis of ischemic brain injury and exert complex interaction effects. Recent studies in rodents have shown that cell apoptosis is significantly increased in 24–72 hr, and this effect lasts up to 7 days after ischemia (J. Chen et al, ; Liu et al, ; Lv et al, ; Y. Sun et al, ), which indicates that apoptosis may be an important mechanism underlying ischemic stroke.…”

3D Culture of Bone Marrow-Derived Mesenchymal Stem Cells (BMSCs) Could Improve Bone Regeneration in 3D-Printed Porous Ti6Al4V Scaffolds

“…Thus, we believe that BMSCs may promote bone repair up to 5 months. Rosová et al [ 40 ] and Chen et al [ 41 ] reported that hypoxic conditions could improve BMSC survival and tissue regenerative potential in vivo , and the Matrigel hydrogel microenvironment is moderately hypoxic. Similarly, in our scaffold + Matrigel group, Matrigel without BMSCs inside only formed new bone on the surface of the scaffold, not inside (Figures 7(g) and 8(g) ).…”

HIF‑1α attenuates neuronal apoptosis by upregulating EPO expression following cerebral ischemia‑reperfusion injury in a rat MCAO model

“…It has been reported that hypoxic preconditioning increases tolerance to hypoxic-ischemic-induced brain injury and decreases apoptosis by upregulating the expression of HIF-1α (14). Furthermore, hypoxic preconditioning in transplanted bone marrow stromal cells promoted their capability of regeneration and therapeutic potential to treat rat ischemic stroke (15).…”