Instituto de Anatomía, Histología y Patología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile.
Centro de Investigaciones Biomédicas, Facultad de Medicina, Universidad de los Andes, Santiago, Chile.
Cell Tissue Res. 2020 Jul;381(1):141-161. doi: 10.1007/s00441-020-03182-0. Epub 2020 Feb 17.
Foetal onset hydrocephalus is a disease starting early in embryonic life; in many cases it results from a cell junction pathology of neural stem (NSC) and neural progenitor (NPC) cells forming the ventricular zone (VZ) and sub-ventricular zone (SVZ) of the developing brain. This pathology results in disassembling of VZ and loss of NSC/NPC, a phenomenon known as VZ disruption. At the cerebral aqueduct, VZ disruption triggers hydrocephalus while in the telencephalon, it results in abnormal neurogenesis. This may explain why derivative surgery does not cure hydrocephalus. NSC grafting appears as a therapeutic opportunity. The present investigation was designed to find out whether this is a likely possibility. HTx rats develop hereditary hydrocephalus; 30-40% of newborns are hydrocephalic (hyHTx) while their littermates are not (nHTx). NSC/NPC from the VZ/SVZ of nHTx rats were cultured into neurospheres that were then grafted into a lateral ventricle of 1-, 2- or 7-day-old hyHTx. Once in the cerebrospinal fluid, neurospheres disassembled and the freed NSC homed at the areas of VZ disruption. A population of homed cells generated new multiciliated ependyma at the sites where the ependyma was missing due to the inherited pathology. Another population of NSC homed at the disrupted VZ differentiated into βIII-tubulin+ spherical cells likely corresponding to neuroblasts that progressed into the parenchyma. The final fate of these cells could not be established due to the protocol used to label the grafted cells. The functional outcomes of NSC grafting in hydrocephalus remain open. The present study establishes an experimental paradigm of NSC/NPC therapy of foetal onset hydrocephalus, at the etiologic level that needs to be further explored with more analytical methodologies.
胎儿期起病的脑积水是一种在胚胎早期就开始的疾病；在许多情况下，它是由于神经干细胞（NSC）和神经祖细胞（NPC）形成脑室区（VZ）和脑室下区（SVZ）的细胞连接病理学引起的。这种病理学导致 VZ 解体和 NSC/NPC 的丧失，这种现象称为 VZ 破坏。在脑导水管，VZ 破坏引发脑积水，而在端脑，则导致异常神经发生。这也许可以解释为什么衍生手术不能治愈脑积水。NSC 移植似乎是一种治疗机会。本研究旨在探讨这是否是一种可能的情况。HTx 大鼠患有遗传性脑积水；30-40%的新生大鼠为脑积水（hyHTx），而其同窝仔鼠则不是（nHTx）。来自 nHTx 大鼠 VZ/SVZ 的 NSC/NPC 被培养成神经球，然后移植到 1、2 或 7 天大的 hyHTx 大鼠的侧脑室中。一旦进入脑脊液，神经球解体，自由的 NSC 归巢到 VZ 破坏的区域。归巢细胞的一部分在因遗传病理学而缺失的室管膜部位生成新的多纤毛室管膜。另一部分归巢到破坏的 VZ 的 NSC 分化为βIII-微管蛋白+球形细胞，可能对应于因进入实质而进展的神经母细胞。由于用于标记移植细胞的方案，无法确定这些细胞的最终命运。NSC 移植治疗脑积水的功能结果仍然存在。本研究建立了胎儿期起病的脑积水 NSC/NPC 治疗的实验范例，处于需要进一步用更多分析方法探索的病因学水平。
