Neuroprotective Effects of Mesenchymal Stem Cells Derived from Human Embryonic Stem Cells in Transient Focal Cerebral Ischemia in Rats

Abstract

Embryonic mesenchymal stem cells (eMSCs) were first derived from human embryonic stem cells (hESCs) overexpressing green fluorescence protein (GFP). They expressed CD29, CD44, CD73, CD105, CD166 and nestin, but not CD34, CD45, CD106 SSEA-4 or Oct3/4. Twenty million eMSCs in 1 mL of phosphate-buffered saline (PBS) were injected into the femoral veins of spontaneously hypertensive rats after transient middle cerebral artery occlusion. The migration and differentiation of the eMSCs in the ischemic brain were analyzed. The results revealed that eMSCs migrated to the infarction region and differentiated into neurons, which were positive for b-tubulin III, microtubule-associated protein 2 (MAP2), HuC, neurofilament and human nuclear antibody, and to vascular endothelial cells, which were positive for von Willebrand factor (vWF). The transplanted cells survived in the infarction region for at least 4 weeks. Adhesive removal function significantly improved in the first week after cell transplantation, and rotarod motor function significantly improved starting from the second week. The infarction volume in the eMSC group was significantly smaller than that in the PBS control group at 4 weeks after infusion. The results of this study show that when administered intravenously, eMSCs differentiated into neuronal and endothelial cells, reduced the infarction volume, and improved behavioral functional outcome significantly in transient focal cerebral ischemia.

Optimization of time for neural stem cells transplantation for brain stroke in rats

“…In both the studies, the beneficial effect of cell transplantation was attributed to multiple factors including the release of trophic factors, especially vascular endothelial growth factor (VEGF) and angiogenesis besides timing of cell injection. Paracrine release of neuroprotective, angiogenic and pro-survival trophic factors has also been reported by many other research groups as central to the therapeutic benefits of cell transplantation therapy for stroke albeit with variation in the expression profile of the trophic factors being specific to the cell type used engraftment (8,9,15,39). The bioactive molecules released by the transplanted cells not only promote their own survival but also participate in the endogenous repair mechanisms by augmenting survival of the host cells in the vicinity.…”

“…Noticeable amongst these are neural stem cells (3,4), bone marrow stem cells (3,5,6), cord blood derived MSCs (7,8), adipose tissue derived (5), embryonic stem cells and their derivatives (9), and induced pluripotent stem cells (iPSCs) (10,11). Nevertheless, ease of availability without moral and ethical strings and differentiation capacity to adopt desired phenotype are vital issues for the search of ideal donor cells for transplantation therapy.…”

In vivo MRI tracking of iron oxide nanoparticle-labeled human mesenchymal stem cells in limb ischemia

“…36 We noted that many migratory Prussian blue-positive cells were positive for VWF staining, and the results were in accordance with previous studies in that the migrated hMSCs differentiated into vascular endothelial cells, which were positive for VWF. 37,38 Nevertheless, there were several limitations in this preliminary study. First, we did not examine the multi-potency ability of APTS-MNP-labeled MSCs in vitro.…”

Embryonic Stem Cell-Derived Multipotent Mesenchymal Stromal Cell Therapy Following Focal Ischemia in the Rat

“…For example, we observed a dramatic reduction in GFP-labelled cells between two and four weeks after post-stroke intravenous hES-MSC injection (Liu et al 2009). Human MSCs transplanted into ischemic mouse hippocampus survived for fewer than seven days (Ohtaki et al 2008).…”

“…Our laboratory has transplanted hES-MSCs intravenously into spontaneously hypertensive rats 24 hours after 1 hour MCAO (Liu et al 2009). The cells were labelled with green fluorescent protein so that the survival, migration and differentiation patterns of the engrafted cells could be monitored.…”