Berryer Martin H, Tegtmeyer Matthew, Binan Loïc, Valakh Vera, Nathanson Anna, Trendafilova Darina, Crouse Ethan, Klein Jenny A, Meyer Daniel, Pietiläinen Olli, Rapino Francesca, Farhi Samouil L, Rubin Lee L, McCarroll Steven A, Nehme Ralda, Barrett Lindy E
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
iScience. 2023 May 30;26(7):106995. doi: 10.1016/j.isci.2023.106995. eCollection 2023 Jul 21.
Emerging evidence of species divergent features of astrocytes coupled with the relative inaccessibility of human brain tissue underscore the utility of human pluripotent stem cell (hPSC) technologies for the generation and study of human astrocytes. However, existing approaches for hPSC-astrocyte generation are typically lengthy or require intermediate purification steps. Here, we establish a rapid and highly scalable method for generating functional human induced astrocytes (hiAs). These hiAs express canonical astrocyte markers, respond to pro-inflammatory stimuli, exhibit ATP-induced calcium transients and support neuronal network development. Moreover, single-cell transcriptomic analyses reveal the generation of highly reproducible cell populations across individual donors, mostly resembling human fetal astrocytes. Finally, hiAs generated from a trisomy 21 disease model identify expected alterations in cell-cell adhesion and synaptic signaling, supporting their utility for disease modeling applications. Thus, hiAs provide a valuable and practical resource for the study of basic human astrocyte function and dysfunction in disease.
越来越多的证据表明星形胶质细胞具有物种差异特征，再加上人类脑组织相对难以获取，这凸显了人类多能干细胞（hPSC）技术在生成和研究人类星形胶质细胞方面的实用性。然而，现有的hPSC生成星形胶质细胞的方法通常耗时较长或需要中间纯化步骤。在此，我们建立了一种快速且高度可扩展的方法来生成功能性人类诱导星形胶质细胞（hiAs）。这些hiAs表达典型的星形胶质细胞标志物，对促炎刺激有反应，表现出ATP诱导的钙瞬变，并支持神经元网络发育。此外，单细胞转录组分析揭示了不同个体供体中高度可重复的细胞群体的产生，这些细胞群体大多类似于人类胎儿星形胶质细胞。最后，从21三体疾病模型生成的hiAs确定了细胞间粘附和突触信号传导的预期改变，支持了它们在疾病建模应用中的实用性。因此，hiAs为研究人类星形胶质细胞在疾病中的基本功能和功能障碍提供了宝贵且实用的资源。
