Generation of ventralized human thalamic organoids with thalamic reticular nucleus.
Generation of ventralized human thalamic organoids with thalamic reticular nucleus.
复制标题
具有丘脑网状核的腹侧人类丘脑类器官的生成。
DOI：
10.1016/j.stem.2023.03.007
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发表时间：
2023
期刊：
影响因子：
23.9
通讯作者：
Park,In-Hyun
中科院分区：
文献类型：
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作者：
Kiral,FerdiRidvan;Cakir,Bilal;Tanaka,Yoshiaki;Kim,Jonghun;Yang,WooSub;Wehbe,Fabien;Kang,Young-Jin;Zhong,Mei;Sancer,Gizem;Lee,Sang-Hun;Xiang,Yangfei;Park,In-Hyun
人脑有机体为模拟人脑发育和病理的多个方面提供了独特的平台。然而，目前的脑器官系统大多缺乏分辨率来概括具有次区域特征的更精细的大脑结构的发展，包括丘脑中功能不同的核。在这里，我们报告了一种将人类胚胎干细胞(HESCs)转化为具有转录多样性核身份的腹侧丘脑器官(VTho)的方法。值得注意的是，单细胞RNA测序显示了以前未实现的丘脑模式，具有丘脑网状核(TRN)的特征，即位于丘脑腹侧的GABA能核。利用vThos，我们探索了TRN特异的疾病相关基因补丁结构域1(PTCHD1)和受体酪氨酸蛋白激酶(ERBB4)在人类丘脑发育过程中的功能。PTCHD1或ERBB4的扰动损害了vThos的神经元功能，尽管不影响整个丘脑谱系的发育。总而言之，vThos为理解人类大脑丘脑中特定核团的发育和病理提供了一个实验模型。
Human brain organoids provide unique platforms for modeling several aspects of human brain development and pathology. However, current brain organoid systems mostly lack the resolution to recapitulate the development of finer brain structures with subregional identity, including functionally distinct nuclei in the thalamus. Here, we report a method for converting human embryonic stem cells (hESCs) into ventral thalamic organoids (vThOs) with transcriptionally diverse nuclei identities. Notably, single-cell RNA sequencing revealed previously unachieved thalamic patterning with a thalamic reticular nucleus (TRN) signature, a GABAergic nucleus located in the ventral thalamus. Using vThOs, we explored the functions of TRN-specific, disease-associated genes patched domain containing 1 (PTCHD1) and receptor tyrosine-protein kinase (ERBB4) during human thalamic development. Perturbations in PTCHD1 or ERBB4 impaired neuronal functions in vThOs, albeit not affecting the overall thalamic lineage development. Together, vThOs present an experimental model for understanding nuclei-specific development and pathology in the thalamus of the human brain.