Neural stem cells derived from primitive mesenchymal stem cells reversed disease symptoms and promoted neurogenesis in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis.
Neural stem cells derived from primitive mesenchymal stem cells reversed disease symptoms and promoted neurogenesis in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis.
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来源于原始间充质干细胞的神经干细胞在多发性硬化症的实验性自身免疫性脑脊髓炎小鼠模型中逆转疾病症状并促进神经发生。
DOI：
10.1186/s13287-021-02563-8
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发表时间：
2021-09-09
影响因子：
7.5
通讯作者：
Chaudhry GR
中科院分区：
文献类型：
--
作者：
Brown C;McKee C;Halassy S;Kojan S;Feinstein DL;Chaudhry GR
多发性硬化（MS）是中枢神经系统（CNS）的自身免疫性炎症性疾病。MS影响数百万人，并造成巨大的经济和社会负担。有没有治愈MS。我们使用了一种新的方法来研究神经干细胞（NSC）的治疗潜力，从人原始间充质干细胞（MSC）在实验性自身免疫性脑脊髓炎（EAE）MS小鼠模型。MSC分化成NSC，标记PKH 26，并注射到EAE小鼠的尾静脉。小鼠的神经行为变化评估了移植细胞对疾病过程的影响。细胞移植后两周处死动物，收集血液、淋巴和CNS组织用于分析。通过流式细胞术在各种组织中追踪移植的细胞。免疫浸润分别用H&E和免疫组化染色进行测定和表征。通过流式细胞术分析免疫调节细胞Treg和Th 17的水平。髓鞘形成通过Luxol固蓝染色和免疫染色来确定。通过免疫组织化学和qRT-PCR分析研究了移植细胞的体内命运以及炎症、星形胶质细胞增生、髓鞘形成、神经、神经保护和神经发生标志物的表达。 MSC衍生的NSC表达特异性神经标志物NESTIN、TUJ 1、VIMENTIN和PAX 6。当移植到EAE小鼠中时，NSC比MSC更能改善EAE症状。移植后分析还显示MSC和NSC归巢到CNS中，伴随着抗炎反应的诱导，导致免疫浸润减少。神经干细胞也调节性T细胞和Th 17细胞水平EAE小鼠与健康对照。Luxol固蓝染色显示治疗小鼠的髓鞘形成显著改善。进一步的分析表明，神经干细胞上调参与髓鞘形成和神经保护的基因，但下调炎症和星形胶质细胞增生的基因比MSC更显着。重要的是，NSC分化为神经衍生物并促进神经发生，可能通过调节BDNF和FGF信号通路。NSC移植通过诱导抗炎反应和促进EAE疾病动物的髓鞘形成、神经保护和神经发生来逆转疾病过程。这些有希望的结果提供了一个基础的临床研究，以治疗MS使用神经干细胞来源于原始的MSC。在线版本包含补充材料，可通过10.1186/s13287-021-02563-8获得。
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS). MS affects millions of people and causes a great economic and societal burden. There is no cure for MS. We used a novel approach to investigate the therapeutic potential of neural stem cells (NSCs) derived from human primitive mesenchymal stem cells (MSCs) in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS. MSCs were differentiated into NSCs, labeled with PKH26, and injected into the tail vein of EAE mice. Neurobehavioral changes in the mice assessed the effect of transplanted cells on the disease process. The animals were sacrificed two weeks following cell transplantation to collect blood, lymphatic, and CNS tissues for analysis. Transplanted cells were tracked in various tissues by flow cytometry. Immune infiltrates were determined and characterized by H&E and immunohistochemical staining, respectively. Levels of immune regulatory cells, Treg and Th17, were analyzed by flow cytometry. Myelination was determined by Luxol fast blue staining and immunostaining. In vivo fate of transplanted cells and expression of inflammation, astrogliosis, myelination, neural, neuroprotection, and neurogenesis markers were investigated by using immunohistochemical and qRT-PCR analysis. MSC-derived NSCs expressed specific neural markers, NESTIN, TUJ1, VIMENTIN, and PAX6. NSCs improved EAE symptoms more than MSCs when transplanted in EAE mice. Post-transplantation analyses also showed homing of MSCs and NSCs into the CNS with concomitant induction of an anti-inflammatory response, resulting in reducing immune infiltrates. NSCs also modulated Treg and Th17 cell levels in EAE mice comparable to healthy controls. Luxol fast blue staining showed significant improvement in myelination in treated mice. Further analysis showed that NSCs upregulated genes involved in myelination and neuroprotection but downregulated inflammatory and astrogliosis genes more significantly than MSCs. Importantly, NSCs differentiated into neural derivatives and promoted neurogenesis, possibly by modulating BDNF and FGF signaling pathways. NSC transplantation reversed the disease process by inducing an anti-inflammatory response and promoting myelination, neuroprotection, and neurogenesis in EAE disease animals. These promising results provide a basis for clinical studies to treat MS using NSCs derived from primitive MSCs. The online version contains supplementary material available at 10.1186/s13287-021-02563-8.
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影响因子：
7.5
作者：
Bravo B;Gallego MI;Flores AI;Bornstein R;Puente-Bedia A;Hernández J;de la Torre P;García-Zaragoza E;Perez-Tavarez R;Grande J;Ballester A;Ballester S
通讯作者：
Ballester S
影响因子：
1.6
作者：
Alghwiri, Alia A.;Jamali, Fatima;Awidi, Abdalla
通讯作者：
Awidi, Abdalla
影响因子：
5.3
作者：
Duffy, Samuel S.;Keating, Brooke A.;Moalem-Taylor, Gila
通讯作者：
Moalem-Taylor, Gila
影响因子：
5.6
作者：
Kanakasabai, Saravanan;Casalini, Eli;Bright, John J.
通讯作者：
Bright, John J.
影响因子：
5.4
作者：
Glatigny, Simon;Bettelli, Estelle
通讯作者：
Bettelli, Estelle