Viral mediated knockdown of GATA6 in SMA iPSC-derived astrocytes prevents motor neuron loss and microglial activation.
Viral mediated knockdown of GATA6 in SMA iPSC-derived astrocytes prevents motor neuron loss and microglial activation.
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脊髓性肌萎缩症(SMA)是一种儿童遗传性疾病，其特征是脊髓运动神经元的严重丧失以及随后的肌肉萎缩和死亡。尽管运动神经元丢失的机制尚不完全清楚，但来自我们和其他人的数据支持神经胶质细胞参与疾病病理的观点。GATA6是一种转录因子，我们之前已经证明在星形胶质细胞中上调，它受存活运动神经元(SMN)的负调控，并可以增加炎症调节因子NFκB的表达。在本研究中，我们发现上调的GATA6参与了脊髓样星形星形细胞的激活、促炎配体的产生和神经毒性的增加。通过慢病毒感染降低GATA6在SMA星形胶质细胞中的表达可将这些影响改善到健康对照水平。此外，我们发现SMA星形胶质细胞有助于SMA小胶质细胞的吞噬，而慢病毒介导的GATA6基因敲除再次降低了SMA小胶质细胞的吞噬功能。总之，这些数据确定了GATA6在SMA星形胶质细胞病理中的作用，并进一步强调了胶质细胞作为SMA治疗干预的重要靶点。GATA6在SMA星形胶质细胞中表达上调，并与胶质细胞活化增加、促炎配体产生增加、小胶质细胞形态和吞噬功能改变以及运动神经元毒性有关。
Spinal muscular atrophy (SMA), a pediatric genetic disorder, is characterized by the profound loss of spinal cord motor neurons and subsequent muscle atrophy and death. Although the mechanisms underlying motor neuron loss are not entirely clear, data from our work and others support the idea that glial cells contribute to disease pathology. GATA6, a transcription factor that we have previously shown to be upregulated in SMA astrocytes, is negatively regulated by SMN (survival motor neuron) and can increase the expression of inflammatory regulator NFκB. In this study, we identified upregulated GATA6 as a contributor to increased activation, pro‐inflammatory ligand production, and neurotoxicity in spinal‐cord patterned astrocytes differentiated from SMA patient induced pluripotent stem cells. Reducing GATA6 expression in SMA astrocytes via lentiviral infection ameliorated these effects to healthy control levels. Additionally, we found that SMA astrocytes contribute to SMA microglial phagocytosis, which was again decreased by lentiviral‐mediated knockdown of GATA6. Together these data identify a role of GATA6 in SMA astrocyte pathology and further highlight glia as important targets of therapeutic intervention in SMA. GATA6 is upregulated in SMA astrocytes and is associated with increased glial activation, enhanced pro‐inflammatory ligand production, altered microglial morphology and phagocytosis, and motor neuron toxicity.
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影响因子：
4.6
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