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首页> 外文期刊>Stem Cell Research & Therapy >Neurogenic and neuro-protective potential of a novel subpopulation of peripheral blood-derived CD133+ ABCG2+CXCR4+ mesenchymal stem cells: development of autologous cell-based therapeutics for traumatic brain injury
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Neurogenic and neuro-protective potential of a novel subpopulation of peripheral blood-derived CD133+ ABCG2+CXCR4+ mesenchymal stem cells: development of autologous cell-based therapeutics for traumatic brain injury

机译：外周血源性CD133 + ABCG2 + CXCR4 +间充质干细胞的新型亚群的神经源性和神经保护性潜力：基于自体细胞的创伤性脑损伤治疗药物的开发

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Introduction Nervous system injuries comprise a diverse group of disorders that include traumatic brain injury (TBI). The potential of mesenchymal stem cells (MSCs) to differentiate into neural cell types has aroused hope for the possible development of autologous therapies for central nervous system injury. Methods In this study we isolated and characterized a human peripheral blood derived (HPBD) MSC population which we examined for neural lineage potential and ability to migrate in vitro and in vivo. HPBD CD133+, ATP-binding cassette sub-family G member 2 (ABCG2)+, C-X-C chemokine receptor type 4 (CXCR4)+ MSCs were differentiated after priming with β-mercaptoethanol (β-ME) combined with trans-retinoic acid (RA) and culture in neural basal media containing basic fibroblast growth factor (FGF2) and epidermal growth factor (EGF) or co-culture with neuronal cell lines. Differentiation efficiencies in vitro were determined using flow cytometry or fluorescent microscopy of cytospins made of FACS sorted positive cells after staining for markers of immature or mature neuronal lineages. RA-primed CD133+ABCG2+CXCR4+ human MSCs were transplanted into the lateral ventricle of male Sprague-Dawley rats, 24 hours after sham or traumatic brain injury (TBI). All animals were evaluated for spatial memory performance using the Morris Water Maze (MWM) Test. Histological examination of sham or TBI brains was done to evaluate MSC survival, migration and differentiation into neural lineages. We also examined induction of apoptosis at the injury site and production of MSC neuroprotective factors. Results CD133+ABCG2+CXCR4+ MSCs consistently expressed markers of neural lineage induction and were positive for nestin, microtubule associated protein-1β (MAP-1β), tyrosine hydroxylase (TH), neuron specific nuclear protein (NEUN) or type III beta-tubulin (Tuj1). Animals in the primed MSC treatment group exhibited MWM latency results similar to the uninjured (sham) group with both groups showing improvements in latency. Histological examination of brains of these animals showed that in uninjured animals the majority of MSCs were found in the lateral ventricle, the site of transplantation, while in TBI rats MSCs were consistently found in locations near the injury site. We found that levels of apoptosis were less in MSC treated rats and that MSCs could be shown to produce neurotropic factors as early as 2 days following transplantation of cells. In TBI rats, at 1 and 3 months post transplantation cells were generated which expressed markers of neural lineages including immature as well as mature neurons. Conclusions These results suggest that PBD CD133+ABCG2+CXCR4+ MSCs have the potential for development as an autologous treatment for TBI and neurodegenerative disorders and that MSC derived cell products produced immediately after transplantation may aid in reducing the immediate cognitive defects of TBI.
机译：简介神经系统损伤包括多种疾病，包括脑外伤（TBI）。间充质干细胞（MSCs）分化为神经细胞类型的潜力为可能发展中枢神经系统损伤的自体疗法引起了希望。方法在本研究中，我们分离并鉴定了人类外周血来源（HPBD）MSC群体，我们研究了其神经谱系潜能以及在体内和体外迁移的能力。在用β-巯基乙醇（β-ME）和反式维甲酸（RA）引发后，分化出了HPBD CD133 +，ATP结合盒G成员2亚家族（ABCG2）+，CXC趋化因子受体4型（CXCR4）+ MSC。在含有碱性成纤维细胞生长因子（FGF2）和表皮生长因子（EGF）的神经基础培养基中培养或与神经元细胞系共培养。在对未成熟或成熟的神经元谱系进行染色后，使用流式细胞术或荧光显微镜检查由FACS分选的阳性细胞制成的细胞纺锤体，测定体外分化效率。在假手术或脑外伤（TBI）后24小时，将RA引发的CD133 + ABCG2 + CXCR4 +人MSC移植到雄性Sprague-Dawley大鼠的侧脑室。使用莫里斯水迷宫（MWM）测试评估所有动物的空间记忆性能。对假手术或TBI脑进行组织学检查，以评估MSC的存活，迁移以及向神经谱系的分化。我们还检查了损伤部位的凋亡诱导和MSC神经保护因子的产生。结果CD133 + ABCG2 + CXCR4 + MSC始终表达神经谱系诱导标记，巢蛋白，微管相关蛋白-1β（MAP-1β），酪氨酸羟化酶（TH），神经元特异性核蛋白（NEUN）或III型β-微管蛋白阳性。 （Tuj1）。致敏的MSC治疗组中的动物表现出MWM潜伏期结果，与未受伤（假）组相似，两组均显示潜伏期得到改善。对这些动物的大脑进行组织学检查表明，在未受伤的动物中，大多数MSCs在侧脑室即移植部位发现，而在TBI大鼠中，MSCs始终在损伤部位附近发现。我们发现在MSC处理的大鼠中凋亡水平较低，并且可以证明MSC最早在细胞移植后2天就产生了神经营养因子。在TBI大鼠中，移植后1和3个月产生的细胞表达神经谱系的标记，包括未成熟和成熟的神经元。结论这些结果表明，PBD CD133 + ABCG2 + CXCR4 + MSCs具有发展潜力，可作为TBI和神经退行性疾病的自体疗法，并且移植后立即产生的MSC衍生细胞产物可能有助于减少TBI的即刻认知缺陷。

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