Departamento de Biología Celular, Genética y Fisiología, Universidad de Málaga, Campus de Teatinos, 29071, Malaga, Spain.
Instituto de Investigación Biomédica de Málaga (IBIMA), Malaga, Spain.
Stem Cell Res Ther. 2020 Mar 17;11(1):121. doi: 10.1186/s13287-020-01626-6.
In obstructive congenital hydrocephalus, cerebrospinal fluid accumulation is associated with high intracranial pressure and the presence of periventricular edema, ischemia/hypoxia, damage of the white matter, and glial reactions in the neocortex. The viability and short time effects of a therapy based on bone marrow-derived mesenchymal stem cells (BM-MSC) have been evaluated in such pathological conditions in the hyh mouse model.
BM-MSC obtained from mice expressing fluorescent mRFP1 protein were injected into the lateral ventricle of hydrocephalic hyh mice at the moment they present a very severe form of the disease. The effect of transplantation in the neocortex was compared with hydrocephalic hyh mice injected with the vehicle and non-hydrocephalic littermates. Neural cell populations and the possibility of transdifferentiation were analyzed. The possibility of a tissue recovering was investigated using H High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance (H HR-MAS NMR) spectroscopy, thus allowing the detection of metabolites/osmolytes related with hydrocephalus severity and outcome in the neocortex. An in vitro assay to simulate the periventricular astrocyte reaction conditions was performed using BM-MSC under high TNFα level condition. The secretome in the culture medium was analyzed in this assay.
Four days after transplantation, BM-MSC were found undifferentiated and scattered into the astrocyte reaction present in the damaged neocortex white matter. Tissue rejection to the integrated BM-MSC was not detected 4 days after transplantation. Hyh mice transplanted with BM-MSC showed a reduction in the apoptosis in the periventricular neocortex walls, suggesting a neuroprotector effect of the BM-MSC in these conditions. A decrease in the levels of metabolites/osmolytes in the neocortex, such as taurine and neuroexcytotoxic glutamate, also indicated a tissue recovering. Under high TNFα level condition in vitro, BM-MSC showed an upregulation of cytokine and protein secretion that may explain homing, immunomodulation, and vascular permeability, and therefore the tissue recovering.
BM-MSC treatment in severe congenital hydrocephalus is viable and leads to the recovery of the severe neurodegenerative conditions in the neocortex. NMR spectroscopy allows to follow-up the effects of stem cell therapy in hydrocephalus.
在梗阻性先天性脑积水，脑脊液的积累与颅内压增高和存在的脑室周围水肿、缺血/缺氧、脑白质损伤和神经胶质反应在新皮层。基于骨髓间充质干细胞（BM-MSC）的治疗的可行性和短期效果已被评估在这种病理条件下的 hyh 小鼠模型。
从表达红色荧光蛋白 1 蛋白的小鼠中获得 BM-MSC，在 hyh 小鼠出现非常严重的疾病形式时，将其注入侧脑室。移植对新皮层的影响与注射载体的 hyh 脑积水小鼠和非脑积水同窝仔鼠进行了比较。分析了神经细胞群体和转分化的可能性。利用高分辨率魔角旋转核磁共振（H HR-MAS NMR）光谱学来研究组织恢复的可能性，从而可以检测到与新皮层脑积水严重程度和结果相关的代谢物/渗透物。在高 TNFα水平条件下，用 BM-MSC 模拟室管膜星形胶质细胞反应条件进行体外检测。在该检测中分析了培养上清液中的分泌组。
移植后 4 天，发现 BM-MSC 未分化并散布在受损新皮层白质中的星形胶质细胞反应中。移植后 4 天未检测到对整合的 BM-MSC 的组织排斥。移植 BM-MSC 的 hyh 小鼠在脑室周围新皮层壁的细胞凋亡减少，表明 BM-MSC 在这些条件下具有神经保护作用。新皮层中代谢物/渗透物水平的降低，如牛磺酸和神经兴奋毒性谷氨酸，也表明组织恢复。在体外高 TNFα水平条件下，BM-MSC 表现出细胞因子和蛋白分泌的上调，这可能解释了归巢、免疫调节和血管通透性，从而促进了组织恢复。
在严重先天性脑积水中，BM-MSC 治疗是可行的，并导致新皮层严重神经退行性病变的恢复。NMR 光谱学允许对干细胞治疗脑积水的效果进行随访。
