Transplantation of human bone marrow stem cells into symptomatic ALS mice enhances structural and functional blood-spinal cord barrier repair.
Transplantation of human bone marrow stem cells into symptomatic ALS mice enhances structural and functional blood-spinal cord barrier repair.
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DOI：
10.1016/j.expneurol.2018.08.012
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发表时间：
2018-12
影响因子：
5.3
通讯作者：
Borlongan CV
中科院分区：
文献类型：
--
作者：
Garbuzova-Davis S;Haller E;Navarro S;Besong TE;Boccio KJ;Hailu S;Khatib M;Sanberg PR;Appel SH;Borlongan CV
越来越多的证据表明，ALS患者和疾病动物模型中的血脑屏障（BBB）和血脊髓屏障（BSCB）发生了变化，主要是内皮细胞（EC）损伤。通过细胞移植替代EC修复CNS中改变的屏障可能是ALS的新治疗方法。最近，我们通过静脉内给予不同剂量的未修饰的人骨髓CD34+（hBM34+）细胞到有症状的ALS小鼠中，证明了对BSCB修复的积极作用。然而，这些移植细胞对有症状的ALS小鼠微血管完整性的具体益处仍不清楚。本研究的目的是确定结构和功能的脊髓毛细血管的完整性在有症状的ALS小鼠静脉注射hBM 34+细胞后。13周龄的G93A小鼠静脉内接受三种不同细胞剂量（5×104、5×105或1×106）中的一种，并在17周龄（移植后4周）处以安乐死。对照组为培养基处理和非携带突变型SOD1基因小鼠。在颈脊髓和腰脊髓中进行毛细血管超微结构（电子显微镜）、免疫组织化学（层粘连蛋白和HuNu）和组织学（髓鞘和毛细血管密度）分析。通过注射伊文思蓝（EB）测定脊髓中的毛细血管通透性。结果显示，接受高剂量1×106个细胞的ALS小鼠主要脊髓中的超微结构毛细血管形态显著恢复，基底膜完整性改善，轴突髓鞘连贯性增强，毛细血管密度稳定。此外，在这些小鼠中确定了实质EB水平的实质性降低，证实了我们先前关于毛细血管通透性的结果。此外，通过HuNu标记物在处死的晚期症状小鼠的血涂片中检测到移植的细胞。总之，这些结果提供了新的证据，即在最佳剂量下的未修饰的骨髓造血干细胞治疗可能有利于ALS晚期受损BSCB的结构和功能修复，可能通过增加运动神经元存活延迟疾病进展。
Accumulating evidence shows alterations in the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) in ALS patients and in animal models of disease, mainly by endothelial cell (EC) damage. Repair of the altered barrier in the CNS by replacement of ECs via cell transplantation may be a new therapeutic approach for ALS. Recently, we demonstrated positive effects towards BSCB repair by intravenous administration of unmodified human bone marrow CD34+ (hBM34+) cells at different doses into symptomatic ALS mice. However, particular benefits of these transplanted cells on microvascular integrity in symptomatic ALS mice are still unclear. The aim of the present study was to determine the structural and functional spinal cord capillary integrity in symptomatic ALS mice after intravenous administration of hBM34+ cells. The G93A mice at 13 weeks of age intravenously received one of three different cell doses (5×104, 5×105, or 1×106) and were euthanized at 17 weeks of age (4 weeks post-transplant). Control groups were media-treated and non-carrier mutant SOD1 gene mice. Capillary ultrastructural (electron microscopy), immunohistochemical (laminin and HuNu), and histological (myelin and capillary density) analyses were performed in the cervical and lumbar spinal cords. Capillary permeability in the spinal cords was determined by Evans Blue (EB) injection. Results showed significant restoration of ultrastructural capillary morphology, improvement of basement membrane integrity, enhancement of axonal myelin coherence, and stabilization of capillary density in the spinal cords primarily of ALS mice receiving the high dose of 1×106 cells. Moreover, substantial reduction of parenchymal EB levels was determined in these mice, confirming our previous results on capillary permeability. Additionally, transplanted cells were detected in blood smears of sacrificed late symptomatic mice by HuNu marker. Altogether, these results provide novel evidence that unmodified bone marrow hematopoietic stem cell treatment at optimal dose might be beneficial for structural and functional repair of the damaged BSCB in advanced stage of ALS potentially resulting in delayed disease progression by increased motor neuron survival.
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影响因子：
2.9
作者：
Ay, Ilknur;Francis, Jonathan W.;Brown, Robert H., Jr.
通讯作者：
Brown, Robert H., Jr.
影响因子：
9.3
作者：
Cui Y;Masaki K;Yamasaki R;Imamura S;Suzuki SO;Hayashi S;Sato S;Nagara Y;Kawamura MF;Kira J
通讯作者：
Kira J
影响因子：
7.4
作者：
D'Amico, Emanuele;Factor-Litvak, Pam;Santella, Regina M.;Mitsumoto, Hiroshi
通讯作者：
Mitsumoto, Hiroshi
影响因子：
2.5
作者：
Garbuzova-Davis, Svitlana;Haller, Edward;Williams, Stephanie N.;Haim, Eithan D.;Tajiri, Naoki;Hernandez-Ontiveros, Diana G.;Frisina-Deyo, Aric;Boffeli, Sean M.;Sanberg, Paul R.;Borlongan, Cesario V.
通讯作者：
Borlongan, Cesario V.
影响因子：
5.3
作者：
Garbuzova-Davis S;Sanberg PR
通讯作者：
Sanberg PR