Genetically modified mesenchymal stem cells (MSCs) promote axonal regeneration and prevent hypersensitivity after spinal cord injury
Genetically modified mesenchymal stem cells (MSCs) promote axonal regeneration and prevent hypersensitivity after spinal cord injury
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DOI：
10.1016/j.expneurol.2013.06.028
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发表时间：
2013-10-01
影响因子：
5.3
通讯作者：
Dietrich, W. Dalton
中科院分区：
文献类型：
--
作者：
Kumagai, Gentaro;Tsoulfas, Pantelis;Dietrich, W. Dalton
神经营养因子和骨髓基质细胞（MSCs）移植都是针对脊髓损伤（SCI）的候选疗法。虽然一些研究已经表明MSC转分化为神经细胞的能力，但其他SCI研究已经提出了抗炎和其他机制，这些机制是建立有益效果的基础。我们移植了经过基因修饰以表达MNTS 1（一种结合TrkA、TrkB和TrkC的多神经营养因子）和p75（NTR）受体或主要结合Trk受体的MSC-MNTS 1/p75（-）的大鼠MSC。在挫伤性SCI后7天，将仅PBS、GFP-MSC、MSC-MNTS 1/GFP或MSC-MNTS 1/p75（-）/GFP递送到损伤中心。与对照SCI大鼠相比，所有移植组均显示炎症和囊腔大小减少。有趣的是，移植MSC-MNTS 1和MSC-MNTS 1/p75（-），而不是幼稚MSC，增强了轴突生长，并显着防止SCI后皮肤过敏。此外，MSC-MNTS 1/p75（-）移植促进了血管生成并改善了胶质瘢痕形成。这些发现表明，用多神经营养因子转导的MSC在促进细胞生长和改善SCI后的感觉功能方面是有效的。这些新的数据也提供了深入了解神经营养因子受体依赖的机制，通过细胞移植导致功能改善后，实验性SCI。(C)2013 Elsevier Inc. All rights reserved.
Neurotrophins and the transplantation of bone marrow-derived stromal cells (MSCs) are both candidate therapies targeting spinal cord injury (SCI). While some studies have suggested the ability of MSCs to transdifferentiate into neural cells, other SCI studies have proposed anti-inflammatory and other mechanisms underlying established beneficial effects. We grafted rat MSCs genetically modified to express MNTS1, a multineurotrophin that binds TrkA, TrkB and TrkC, and p75(NTR) receptors or MSC-MNTS1/p75(-) that binds mainly to the Trk receptors. Seven days after contusive SCI, PBS-only, GFP-MSC, MSC-MNTS1/GFP or MSC-MNTS1/p75(-)/GFP were delivered into the injury epicenter. All transplanted groups showed reduced inflammation and cystic cavity size compared to control SCI rats. Interestingly, transplantation of the MSC-MNTS1 and MSC-MNTS1/p75(-), but not the naive MSCs, enhanced axonal growth and significantly prevented cutaneous hypersensitivity after SCI. Moreover, transplantation of MSC-MNTS1/p75(-) promoted angiogenesis and modified glial scar formation. These findings suggest that MSCs transduced with a multineurotrophin are effective in promoting cell growth and improving sensory function after SCI. These novel data also provide insight into the neurotrophin-receptor dependent mechanisms through which cellular transplantation leads to functional improvement after experimental SCI. (C) 2013 Elsevier Inc. All rights reserved.