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Therapeutic benefits by human mesenchymal stem cells (hMSCs) and Ang-1 gene-modified hMSCs after cerebral ischemia.

ABSTRACT: Transplantation of human mesenchymal stem cells (hMSCs) prepared from adult bone marrow has been reported to ameliorate functional deficits after cerebral artery occlusion in rats. Although several hypotheses to account for these therapeutic effects have been suggested, current thinking is that both neuroprotection and angiogenesis are primarily responsible. In this study, we compared the effects of hMSCs and angiopoietin-1 gene-modified hMSCs (Ang-hMSCs) intravenously infused into rats 6 h after permanent middle cerebral artery occlusion. Magnetic resonance imaging and histologic analyses revealed that rats receiving hMSCs or Ang-hMSCs exhibited comparable reduction in gross lesion volume as compared with the control group. Although both cell types indeed improved angiogenesis near the border of the ischemic lesions, neovascularization and regional cerebral blood flow were greater in some border areas in Ang-hMSC group. Both hMSC- and Ang-hMSC-treated rats showed greater improved functional recovery in the treadmill stress test than did control rats, but the Ang-hMSC group was greater. These results indicate the intravenous administration of genetically modified hMSCs to express angiopoietin has a similar effect on reducing lesion volume as hMSCs, but the Ang-hMSC group showed enhanced regions of increased angiogenesis at the lesion border, and modest additional improvement in functional outcome.

SUBMITTER: Onda T

PROVIDER: S-EPMC2605394 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

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Therapeutic benefits by human mesenchymal stem cells (hMSCs) and Ang-1 gene-modified hMSCs after cerebral ischemia.

Onda Toshiyuki T Honmou Osamu O Harada Kuniaki K Houkin Kiyohiro K Hamada Hirofumi H Kocsis Jeffery D JD

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20070718 2

Transplantation of human mesenchymal stem cells (hMSCs) prepared from adult bone marrow has been reported to ameliorate functional deficits after cerebral artery occlusion in rats. Although several hypotheses to account for these therapeutic effects have been suggested, current thinking is that both neuroprotection and angiogenesis are primarily responsible. In this study, we compared the effects of hMSCs and angiopoietin-1 gene-modified hMSCs (Ang-hMSCs) intravenously infused into rats 6 h afte ...[more]

PMID: 17637706

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Project description:BackgroundA stroke caused by angiostenosis always has a poor prognosis. Bone marrow stromal cells (BMSC) are widely applied in vascular regeneration. Recently, thrombospondin-4 (TSP4) was reported to promote the regeneration of blood vessels and enhance the function of endothelial cells in angiogenesis. In this work, we observed the therapeutic effect of TSP4-overexpressing BMSCs on angiogenesis post-stroke.MethodsWe subcloned the tsp4 gene into a lentivirus expression vector system and harvested the tsp4 lentivirus using 293FT cells. Primary BMSCs were then successfully infected by the tsp4 virus, and overexpression of GFP-fused TSP4 was confirmed by both western blot and immunofluorescence. In vitro, TSP4-overexpressing BMSCs and wild-type BMSCs were co-cultured with human umbilical vein endothelial cells (HUVECs). The expression level of TSP4, vascular endothelial growth factor (VEGF) and transforming growth factor-β (TGF-β) in the supernatant were detected by enzyme-linked immunosorbent assay (ELISA). Wound healing, tube formation and an arterial ring test were performed to estimate the ability of TSP4-overexpressing BMSCs to promote the angiogenesis of endothelial cells. Using a rat permanent middle cerebral artery occlusion (MCAO) model, the effect of TSP4-overexpressing BMSCs on the regeneration of blood vessels was systematically tested by the neurological function score, immunohistochemistry and immunofluorescence staining assays.ResultsOur results demonstrated that TSP4-overexpressing BMSCs largely increased the expression of VEGF, angiopoietin-1 (Ang-1), matrix metalloprotein 9 (MMP9), matrix metalloprotein 2 (MMP2) and p-Cdc42/Rac1 in endothelial cells. TSP4-BMSC treatment notably up-regulated the TGF-β/Smad2/3 signalling pathway in HUVECs. In vivo, the TSP4-BMSC infusion improved the neurological function score of MCAO rats and expanded the expression of the von Willebrand factor (vWF), Ang-1, MMP2 and MMP9 proteins in cerebral ischemic penumbra.ConclusionsOur data illustrate that TSP4-BMSCs can promote the proliferation and migration of endothelial cells and tube formation. We found that TSP4-BMSC infusion can promote the recovery of neural function post-stroke. The tsp4 gene-modified BMSCs provides a better therapeutic effect than that of wild-type BMSCs.

Project description:IntroductionStem cell transplantation is a promising therapeutic strategy for the treatment of stroke. Mesenchymal stem cells (MSCs) are a potential cell source for clinical application because they can be easily obtained and cultivated with a high proliferative capacity. The safety and efficacy of cell therapy depends on the mode of cell administration. To determine the therapeutic potential of intrathecal administration of MSCs by lumbar puncture (LP), we administrated human umbilical cord blood-derived MSCs (hUCB-MSCs) intrathecally into the lumbar spinal cord or intravenously into the tail vein in a rat model of stroke, and then investigated whether hUCB-MSCs could enter the brain, survive, and improve post-stroke neurological functional recovery.MethodshUCB-MSCs (1.0 × 10(6)) were administrated three days after stroke induced by occlusion of the middle cerebral artery. The presence of hUCB-MSCs and their survival and differentiation in the brain tissue of the rats was examined by immunohistochemistry. Recovery of coordination of movement after administration of hUCB-MSCs was examined using a Rotarod test and adhesive-removal test on the 7th, 14th, 21st, and 28th days after ischemia. The volume of ischemic lesions seven days after the experimental procedure was evaluated using 2-3-5-triphenyltetrazolium (TTC) staining.ResultsRats receiving hUCB-MSCs intrathecally by LP had a significantly higher number of migrated cells within the ischemic area when compared with animals receiving cells intravenously. In addition, many of the cells administered intrathecally survived and a subset of them expressed mature neural-lineage markers, including the mature neuron marker NeuN and glial fibrillary acidic protein, typical of astrocytes. Animals that received hUCB-MSCs had significantly improved motor function and reduced ischemic damage when compared with untreated control animals. Regardless of the administration route, the group treated with 1 × 10(6) hUCB-MSCs showed better neurological recovery, without significant differences between the two treatment groups. Importantly, intrathecal administration of 5 × 10(5) hUCB-MSCs significantly reduced ischemic damage, but not in the intravenously treated group. Furthermore, the cells administered intrathecally survived and migrated into the ischemic area more extensively, and differentiated significantly into neurons and astrocytes.ConclusionsTogether, these results indicate that intrathecal administration of MSCs by LP may be useful and feasible for MSCs treatment of brain injuries, such as stroke, or neurodegenerative disorders.

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Therapeutic benefits by human mesenchymal stem cells (hMSCs) and Ang-1 gene-modified hMSCs after cerebral ischemia.

Publications

Therapeutic benefits by human mesenchymal stem cells (hMSCs) and Ang-1 gene-modified hMSCs after cerebral ischemia.

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