1] Department of Biotechnology and Biosciences, University Milan Bicocca, Piazza della Scienza 2, Milano 20126, Italy [2] Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, Milano 20133, Italy.
Cell Death Dis. 2013 Nov 7;4(11):e906. doi: 10.1038/cddis.2013.430.
Mucopolysaccharidosis type II (MPSII or Hunter Syndrome) is a lysosomal storage disorder caused by the deficit of iduronate 2-sulfatase (IDS) activity and characterized by progressive systemic and neurological impairment. As the early mechanisms leading to neuronal degeneration remain elusive, we chose to examine the properties of neural stem cells (NSCs) isolated from an animal model of the disease in order to evaluate whether their neurogenic potential could be used to recapitulate the early phases of neurogenesis in the brain of Hunter disease patients. Experiments here reported show that NSCs derived from the subventricular zone (SVZ) of early symptomatic IDS-knockout (IDS-ko) mouse retained self-renewal capacity in vitro, but differentiated earlier than wild-type (wt) cells, displaying an evident lysosomal aggregation in oligodendroglial and astroglial cells. Consistently, the SVZ of IDS-ko mice appeared similar to the wt SVZ, whereas the cortex and striatum presented a disorganized neuronal pattern together with a significant increase of glial apoptotic cells, suggesting that glial degeneration likely precedes neuronal demise. Interestingly, a very similar pattern was observed in the brain cortex of a Hunter patient. These observations both in vitro, in our model, and in vivo suggest that IDS deficit seems to affect the late phases of neurogenesis and/or the survival of mature cells rather than NSC self-renewal. In particular, platelet-derived growth factor receptor-α-positive (PDGFR-α+) glial progenitors appeared reduced in both the IDS-ko NSCs and in the IDS-ko mouse and human Hunter brains, compared with the respective healthy controls. Treatment of mutant NSCs with IDS or PDGF throughout differentiation was able to increase the number of PDGFR-α+ cells and to reduce that of apoptotic cells to levels comparable to wt. This evidence supports IDS-ko NSCs as a reliable in vitro model of the disease, and suggests the rescue of PDGFR-α+ glial cells as a therapeutic strategy to prevent neuronal degeneration.
黏多糖贮积症 II 型（MPSII 或亨特综合征）是一种溶酶体贮积症，由艾杜糖-2-硫酸酯酶（IDS）活性缺乏引起，其特征是进行性全身和神经功能障碍。由于导致神经元退行性变的早期机制尚不清楚，我们选择检查来自疾病动物模型的神经干细胞（NSC）的特性，以评估它们的神经发生潜力是否可用于重现亨特病患者大脑中的早期神经发生阶段。这里报道的实验表明，源自早期症状性 IDS 敲除（IDS-ko）小鼠侧脑室下区（SVZ）的 NSC 在体外保留自我更新能力，但比野生型（wt）细胞更早分化，在少突胶质细胞和星形胶质细胞中显示出明显的溶酶体聚集。一致地，IDS-ko 小鼠的 SVZ 类似于 wt SVZ，而皮质和纹状体呈现出紊乱的神经元模式，同时胶质细胞凋亡细胞显著增加，表明胶质细胞退行性变可能先于神经元死亡。有趣的是，在亨特病患者的大脑皮质中观察到非常相似的模式。这些观察结果无论是在我们的模型的体外，还是在体内，都表明 IDS 缺乏似乎影响神经发生的晚期阶段和/或成熟细胞的存活，而不是 NSC 的自我更新。特别是，与各自的健康对照相比，血小板衍生生长因子受体-α阳性（PDGFR-α+）神经胶质祖细胞在 IDS-ko NSC 以及 IDS-ko 小鼠和亨特病人类大脑中均减少。在分化过程中用 IDS 或 PDGF 处理突变型 NSC 能够增加 PDGFR-α+细胞的数量，并将凋亡细胞的数量减少至与 wt 相当的水平。这一证据支持 IDS-ko NSC 作为疾病的可靠体外模型，并表明拯救 PDGFR-α+神经胶质细胞是预防神经元退行性变的一种治疗策略。
