Established Stem Cell Model of Spinal Muscular Atrophy Is Applicable in the Evaluation of the Efficacy of Thyrotropin‐Releasing Hormone Analog
Established Stem Cell Model of Spinal Muscular Atrophy Is Applicable in the Evaluation of the Efficacy of Thyrotropin‐Releasing Hormone Analog
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DOI：
10.5966/sctm.2015-0059
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发表时间：
2016-02
影响因子：
6
通讯作者：
Kazuki Ohuchi;M. Funato;Zenichiro Kato;Junko Seki;Chizuru Kawase;Y. Tamai;Y. Ono;Y. Nagahara;Yasuhiro Noda;Tsubasa Kameyama;Shiori Ando;K. Tsuruma;M. Shimazawa;H. Hara;Hideo Kaneko
中科院分区：
文献类型：
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作者：
Kazuki Ohuchi;M. Funato;Zenichiro Kato;Junko Seki;Chizuru Kawase;Y. Tamai;Y. Ono;Y. Nagahara;Yasuhiro Noda;Tsubasa Kameyama;Shiori Ando;K. Tsuruma;M. Shimazawa;H. Hara;Hideo Kaneko
脊髓性肌萎缩症（SMA）是一种以脊髓运动神经元变性为特征的常染色体隐性遗传神经肌肉疾病。这种疾病主要是由运动神经元生存基因1（SMN 1）突变或缺失引起的。目前尚无有效的治疗方法，只能对症治疗。我们在本研究中的目的是建立人SMA衍生的诱导多能干细胞（SMA-iPSC）疾病模型，并测定治疗药物，为开发SMA的新治疗方法做准备。我们从SMA患者的皮肤成纤维细胞中产生了iPSC，并证实它们是多能的和未分化的。SMA‐ iPSC的神经分化缩短了树突和轴突长度，并增加了脊髓运动神经元的凋亡。此外，我们在分化的SMA‐ iPSC中发现了活化的星形胶质细胞。使用该模型，我们证实了促甲状腺素释放激素（TRH）类似物5-氧代-1-脯氨酰-1-组氨酰-1-脯氨酰胺（在临床试验中具有边际效应）治疗可增加SMN蛋白水平。这种增加是通过SMN 2基因的转录激活和糖原合成酶激酶-3 β活性的抑制介导的。最后，TRH类似物处理导致分化的SMA-iPSC中脊髓运动神经元的树突和轴突发育。这些结果表明，这种人体外疾病模型刺激SMA病理学，并揭示了TRH类似物治疗SMA的潜在功效。因此，我们可以使用人SMA‐iPSC模型轻松有效地筛选新型治疗药物，如TRH。
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by the degeneration of spinal motor neurons. This disease is mainly caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene. Currently, no effective treatment is available, and only symptomatic treatment can be provided. Our purpose in the present study was to establish a human SMA‐derived induced pluripotent stem cell (SMA‐iPSC) disease model and assay a therapeutic drug in preparation for the development of a novel treatment of SMA. We generated iPSCs from the skin fibroblasts of a patient with SMA and confirmed that they were pluripotent and undifferentiated. The neural differentiation of SMA‐iPSCs shortened the dendrite and axon length and increased the apoptosis of the spinal motor neurons. In addition, we found activated astrocytes in differentiated SMA‐iPSCs. Using this model, we confirmed that treatment with the thyrotropin‐releasing hormone (TRH) analog, 5‐oxo‐l‐prolyl‐l‐histidyl‐l‐prolinamide, which had marginal effects in clinical trials, increases the SMN protein level. This increase was mediated through the transcriptional activation of the SMN2 gene and inhibition of glycogen synthase kinase‐3β activity. Finally, the TRH analog treatment resulted in dendrite and axon development of spinal motor neurons in differentiated SMA‐iPSCs. These results suggest that this human in vitro disease model stimulates SMA pathology and reveal the potential efficacy of TRH analog treatment for SMA. Therefore, we can screen novel therapeutic drugs such as TRH for SMA easily and effectively using the human SMA‐iPSC model.