GATA3 Promotes the Neural Progenitor State but Not Neurogenesis in 3D Traumatic Injury Model of Primary Human Cortical Astrocytes
GATA3 Promotes the Neural Progenitor State but Not Neurogenesis in 3D Traumatic Injury Model of Primary Human Cortical Astrocytes
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DOI：
10.3389/fncel.2019.00023
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发表时间：
2019-02-11
影响因子：
5.3
通讯作者：
Kizil, Caghan
中科院分区：
文献类型：
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作者：
Celikkaya, Hilal;Cosacak, Mehmet Ilyas;Kizil, Caghan
星形胶质细胞是脊椎动物中枢神经系统中丰富的细胞类型，可以在专门的缝隙中充当神经干细胞，在那里它们结构性地产生新的神经元。然而，在干细胞区外，这些神经胶质细胞并不是神经源性的。虽然哺乳动物中枢神经系统的损伤会导致星形胶质细胞的大量增殖，星形胶质细胞聚集在病变部位形成胶质瘢痕，但并不发生神经再生。因此，一个看似合理的再生治疗方案是将内源性反应性星形胶质细胞诱导到神经源性前体细胞之前的状态，并将它们用作内源性修复的储备库。然而，人们对人类受伤后促进神经前体状态的机制知之甚少。先前发现GATA3是斑马鱼大脑用于损伤依赖的神经前体细胞诱导的一种机制。然而，GATA3在损伤后对人脑星形胶质细胞的影响尚不清楚。因此，在这份报告中，我们研究了在2D和3D培养中，GATA3在原代人脑星形胶质细胞中的过度表达如何影响损伤前后的神经发生潜能。我们发现原代培养的人星形胶质细胞在损伤后不能诱导GATA3。慢病毒介导的GATA3过表达显著增加GFAP/SOX2双阳性星形胶质细胞的数量和神经原因子ASCL1的表达，但不能诱导神经发生，提示GATA3是增强原代人脑星形胶质细胞神经发生潜能所必需的，不足以单独诱导神经发生。
Astrocytes are abundant cell types in the vertebrate central nervous system and can act as neural stem cells in specialized niches where they constitutively generate new neurons. Outside the stem cell niches, however, these glial cells are not neurogenic. Although injuries in the mammalian central nervous system lead to profound proliferation of astrocytes, which cluster at the lesion site to form a gliotic scar, neurogenesis does not take place. Therefore, a plausible regenerative therapeutic option is to coax the endogenous reactive astrocytes to a pre-neurogenic progenitor state and use them as an endogenous reservoir for repair. However, little is known on the mechanisms that promote the neural progenitor state after injuries in humans. Gata3 was previously found to be a mechanism that zebrafish brain uses to injury-dependent induction of neural progenitors. However, the effects of GATA3 in human astrocytes after injury are not known. Therefore, in this report, we investigated how overexpression of GATA3 in primary human astrocytes would affect the neurogenic potential before and after injury in 2D and 3D cultures. We found that primary human astrocytes are unable to induce GATA3 after injury. Lentivirus-mediated overexpression of GATA3 significantly increased the number of GFAP/SOX2 double positive astrocytes and expression of pro-neural factor ASCL1, but failed to induce neurogenesis, suggesting that GATA3 is required for enhancing the neurogenic potential of primary human astrocytes and is not sufficient to induce neurogenesis alone.