Abnormal Neural Progenitor Cells Differentiated from Induced Pluripotent Stem Cells Partially Mimicked Development of TSC2 Neurological Abnormalities.
Abnormal Neural Progenitor Cells Differentiated from Induced Pluripotent Stem Cells Partially Mimicked Development of TSC2 Neurological Abnormalities.
复制标题
DOI：
10.1016/j.stemcr.2017.02.020
复制
发表时间：
2017-04-11
影响因子：
5.9
通讯作者：
Zhang C
中科院分区：
文献类型：
--
作者：
Li Y;Cao J;Chen M;Li J;Sun Y;Zhang Y;Zhu Y;Wang L;Zhang C
结节性硬化症(TSC)是一种以毁灭性和治疗上具有挑战性的神经异常为特征的疾病。然而，目前还缺乏针对TSC的特异性神经前体细胞模型。在这里，使用原始神经干细胞(PNSCs)研究了TSC的病理学，该细胞来自一名在TSC2中出现C.1444-2A和GT；C突变的患者。我们发现，与对照组相比，TSC2 pNSCs具有更高的增殖活性和PAX6的表达。TSC2 pNSCs分化出的神经元胞体增大，突起生长紊乱，细胞间连接异常。TSC2星形胶质细胞饱和密度增加，增殖活性增强。此外，mTOR通路的活性在pNSCs中增强，并在神经元和星形胶质细胞中被诱导。因此，我们的结果表明，TSC2杂合性导致了pNSCs的神经畸形，这表明它的杂合性可能足以导致患者的神经异常的发生。从一名TSC2突变患者中分离出原始神经干细胞，TSC2单倍体不足的神经细胞部分模拟了TSC异常。TSC1/2单倍体不足可能足以导致TSC神经病理。这些细胞为研究疾病机制和筛选新药提供了一个新的模型。在本文中，程和他的同事从一名在TSC2中出现C.1444-2A和GT；C突变的患者分离出原始神经干细胞。这些IPSC来源的神经细胞概括了TSC2缺陷患者的病理生理学，并可用于筛选合适的药物进行个性化治疗。
Tuberous sclerosis complex (TSC) is a disease featuring devastating and therapeutically challenging neurological abnormalities. However, there is a lack of specific neural progenitor cell models for TSC. Here, the pathology of TSC was studied using primitive neural stem cells (pNSCs) from a patient presenting a c.1444-2A>C mutation in TSC2. We found that TSC2 pNSCs had higher proliferative activity and increased PAX6 expression compared with those of control pNSCs. Neurons differentiated from TSC2 pNSCs showed enlargement of the soma, perturbed neurite outgrowth, and abnormal connections among cells. TSC2 astrocytes had increased saturation density and higher proliferative activity. Moreover, the activity of the mTOR pathway was enhanced in pNSCs and induced in neurons and astrocytes. Thus, our results suggested that TSC2 heterozygosity caused neurological malformations in pNSCs, indicating that its heterozygosity might be sufficient for the development of neurological abnormalities in patients. Primitive neural stem cells were isolated from a patient with a TSC2 mutation TSC2 haploinsufficient neuronal cells partially modeled TSC abnormalities TSC1/2 haploinsufficiency might be sufficient to contribute to TSC neuropathology These cells provide a new model to study disease mechanisms and screen new drugs In this article, Cheng and colleagues isolated primitive neural stem cells from a patient presenting a c.1444-2A>C mutation in TSC2. These iPSC-derived neural cells recapitulated the pathophysiology of TSC2-deficient patients and could be used for screening appropriate drugs for personalized therapies.