Endothelial and Astrocytic Support by Human Bone Marrow Stem Cell Grafts into Symptomatic ALS Mice towards Blood-Spinal Cord Barrier Repair.
Endothelial and Astrocytic Support by Human Bone Marrow Stem Cell Grafts into Symptomatic ALS Mice towards Blood-Spinal Cord Barrier Repair.
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DOI：
10.1038/s41598-017-00993-0
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发表时间：
2017-04-13
影响因子：
4.6
通讯作者：
Borlongan CV
中科院分区：
文献类型：
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作者：
Garbuzova-Davis S;Kurien C;Thomson A;Falco D;Ahmad S;Staffetti J;Steiner G;Abraham S;James G;Mahendrasah A;Sanberg PR;Borlongan CV
血管病理，包括血液-中枢神经系统屏障（B-CNS-B）损伤通过内皮细胞（EC）变性，是最近公认的肌萎缩性侧索硬化症（ALS）发病机制的标志。B-CNS-B修复可能是治疗渐冻症的新途径。本研究旨在确定将未经修饰的人骨髓CD34+ (hBM34+)细胞移植到症状性G93A小鼠体内对血脊髓屏障（BSCB）修复的影响。13周龄的G93A小鼠静脉注射三种不同剂量的hBM34+细胞之一。细胞处理、培养基处理和对照小鼠在17周龄时被安乐死。免疫组化（抗人vWF、CD45、GFAP和Iba-1）和运动神经元组织学分析在颈、腰椎脊髓进行。脊髓实质内EB水平决定毛细血管通透性。移植的hBM34+细胞改善了行为疾病的预后，并增强了运动神经元的存活，主要是在高细胞剂量小鼠中。移植细胞分化成内皮细胞并在许多毛细血管内移植。脊髓中星形胶质细胞增生、小胶质细胞增生减少，血管末梢足星形胶质细胞增强，主要发生在高细胞剂量小鼠中。这些小鼠的实质EB水平也显著降低。症状性ALS小鼠EC分化、毛细血管植入、毛细血管通透性降低和血管周围终足星形胶质细胞重建可能代表BSCB修复过程，支持hBM34+细胞移植作为ALS患者未来的治疗策略。
Vascular pathology, including blood-CNS barrier (B-CNS-B) damage via endothelial cell (EC) degeneration, is a recently recognized hallmark of Amyotrophic Lateral Sclerosis (ALS) pathogenesis. B-CNS-B repair may be a new therapeutic approach for ALS. This study aimed to determine effects of transplanted unmodified human bone marrow CD34+ (hBM34+) cells into symptomatic G93A mice towards blood-spinal cord barrier (BSCB) repair. Thirteen weeks old G93A mice intravenously received one of three different doses of hBM34+ cells. Cell-treated, media-treated, and control mice were euthanized at 17 weeks of age. Immunohistochemical (anti-human vWF, CD45, GFAP, and Iba-1) and motor neuron histological analyses were performed in cervical and lumbar spinal cords. EB levels in spinal cord parenchyma determined capillary permeability. Transplanted hBM34+ cells improved behavioral disease outcomes and enhanced motor neuron survival, mainly in high-cell-dose mice. Transplanted cells differentiated into ECs and engrafted within numerous capillaries. Reduced astrogliosis, microgliosis, and enhanced perivascular end-feet astrocytes were also determined in spinal cords, mostly in high-cell-dose mice. These mice also showed significantly decreased parenchymal EB levels. EC differentiation, capillary engraftment, reduced capillary permeability, and re-established perivascular end-feet astrocytes in symptomatic ALS mice may represent BSCB repair processes, supporting hBM34+ cell transplantation as a future therapeutic strategy for ALS patients.