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Thrombospondin-1 modified bone marrow mesenchymal stem cells (BMSCs) promote neurite outgrowth and functional recovery in rats with spinal cord injury.

ABSTRACT: Stem cell therapies are currently gaining momentum in the treatment of spinal cord injury (SCI). However, unsatisfied intrinsic neurite growth capacity constitutes significant obstacles for injured spinal cord repair and ultimately results in neurological dysfunction. The present study assessed the efficacy of thrombospondin-1 (TSP-1), a neurite outgrowth-promoting molecule, modified bone marrow mesenchymal stem cells (BMSCs) on promoting neurite outgrowth in vitro and in vivo of Oxygen-Glucose Deprivation (OGD) treated motor neurons and SCI rat models. The present results demonstrated that the treatment of BMSCs+TSP-1 could promote the neurite length, neuronal survival, and functional recovery after SCI. Additionally, TSP-1 could activate transforming growth factor-?1 (TGF-?1) then induced the smad2 phosphorylation, and expedited the expression of GAP-43 to promote neurite outgrowth. The present study for the first time demonstrated that BMSCs+TSP-1 could promote neurite outgrowth and functional recovery after SCI partly through the TGF-?1/p-Samd2 pathway. The study provided a novel encouraging evidence for the potential treatment of BMSCs modification with TSP-1 in patients with SCI.

SUBMITTER: Pu Y

PROVIDER: S-EPMC5707099 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Thrombospondin-1 modified bone marrow mesenchymal stem cells (BMSCs) promote neurite outgrowth and functional recovery in rats with spinal cord injury.

Pu Yujie Y Meng Ke K Gu Chuanlong C Wang Linlin L Zhang Xiaoming X

Oncotarget 20171024 56

Stem cell therapies are currently gaining momentum in the treatment of spinal cord injury (SCI). However, unsatisfied intrinsic neurite growth capacity constitutes significant obstacles for injured spinal cord repair and ultimately results in neurological dysfunction. The present study assessed the efficacy of thrombospondin-1 (TSP-1), a neurite outgrowth-promoting molecule, modified bone marrow mesenchymal stem cells (BMSCs) on promoting neurite outgrowth <i>in vitro</i> and <i>in vivo</i> of O ...[more]

PMID: 29221205

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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.

Dataset Information

Thrombospondin-1 modified bone marrow mesenchymal stem cells (BMSCs) promote neurite outgrowth and functional recovery in rats with spinal cord injury.

Publications

Thrombospondin-1 modified bone marrow mesenchymal stem cells (BMSCs) promote neurite outgrowth and functional recovery in rats with spinal cord injury.

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