Yeon Gyu-Bum, Jeon Byeong-Min, Yoo Seo Hyun, Kim Dongyun, Oh Seung Soo, Park Sanghyun, Shin Won-Ho, Kim Hyung Wook, Na Dokyun, Kim Dong-Wook, Kim Dae-Sung
Department of Biotechnology, Korea University, 145 Anam-Ro, Seongbuk-Gu, Seoul, 02841, Republic of Korea.
Institute of Animal Molecular Biotechnology, Korea University, 145 Anam-Ro, Seongbuk-Gu, Seoul, 02841, Republic of Korea.
Stem Cell Rev Rep. 2023 Aug;19(6):1890-1906. doi: 10.1007/s12015-023-10536-y. Epub 2023 Apr 17.
Molecular and functional diversity among region-specific astrocytes is of great interest in basic neuroscience and the study of neurological diseases. In this study, we present the generation and characterization of astrocytes from human embryonic stem cells with the characteristics of the ventral midbrain (VM). Fine modulation of WNT and SHH signaling during neural differentiation induced neural precursor cells (NPCs) with high expression of EN1 and NKX6.1, but less expression of FOXA2. Overexpression of nuclear factor IB in NPCs induced astrocytes, thereby maintaining the expression of region-specific genes acquired in the NPC stage. When cocultured with dopaminergic (DA) precursors or DA neurons, astrocytes with VM characteristics (VM-iASTs) promoted the differentiation and survival of DA neurons better than those that were not regionally specified. Transcriptomic analysis showed that VM-iASTs were more closely related to human primary midbrain astrocytes than to cortical astrocytes, and revealed the upregulation of WNT1 and WNT5A, which supports their VM identity and explains their superior activity in DA neurons. Taken together, we hope that VM-iASTs can serve to improve ongoing DA precursor transplantation for Parkinson's disease, and that their transcriptomic data provide a valuable resource for investigating regional diversity in human astrocyte populations.
区域特异性星形胶质细胞之间的分子和功能多样性在基础神经科学和神经疾病研究中备受关注。在本研究中，我们展示了具有腹侧中脑（VM）特征的人胚胎干细胞来源星形胶质细胞的生成及特性。神经分化过程中对WNT和SHH信号的精细调控诱导出高表达EN1和NKX6.1但低表达FOXA2的神经前体细胞（NPCs）。NPCs中核因子IB的过表达诱导星形胶质细胞生成，从而维持在NPC阶段获得的区域特异性基因的表达。当与多巴胺能（DA）前体细胞或DA神经元共培养时，具有VM特征的星形胶质细胞（VM-iASTs）比未进行区域特异性指定的星形胶质细胞更能促进DA神经元的分化和存活。转录组分析表明，VM-iASTs与人原发性中脑星形胶质细胞的关系比与皮质星形胶质细胞的关系更密切，并揭示了WNT1和WNT5A的上调，这支持了它们的VM特性，并解释了它们在DA神经元中的优越活性。综上所述，我们希望VM-iASTs能够用于改善目前针对帕金森病的DA前体细胞移植，并且它们的转录组数据为研究人类星形胶质细胞群体的区域多样性提供了宝贵资源。
