Walsh Ryan, Giacomelli Elisa, Ciceri Gabriele, Rittenhouse Chelsea, Galimberti Maura, Wu Youjun, Muller James, Vezzoli Elena, Jungverdorben Johannes, Zhou Ting, Barker Roger A, Cattaneo Elena, Studer Lorenz, Baggiolini Arianna
bioRxiv. 2023 Feb 17:2023.02.17.528906. doi: 10.1101/2023.02.17.528906.
Mammalian outer radial glia (oRG) emerge as cortical progenitor cells that directly support the development of an enlarged outer subventricular zone (oSVZ) and, in turn, the expansion of the neocortex. The generation of oRG is essential to model and investigate the underlying mechanisms of human neocortical development and expansion. By activating the STAT3 pathway using LIF, which is not produced in guided cortical organoids, we developed a cerebral organoid differentiation method from human pluripotent stem cells (hPSCs) that recapitulates the expansion of a progenitor pool into the oSVZ. The structured oSVZ is composed of progenitor cells expressing specific oRG markers such as , which closely matches human oRG . In this microenvironment, cortical neurons showed faster maturation with enhanced metabolic and functional activity. Incorporation of hPSC-derived brain vascular LIF- producing pericytes in cerebral organoids mimicked the effects of LIF treatment. These data indicate that the cellular complexity of the cortical microenvironment, including cell-types of the brain vasculature, favors the appearance of oRG and provides a platform to routinely study oRG in hPSC-derived brain organoids.
哺乳动物的外侧放射状胶质细胞（oRG）作为皮质祖细胞出现，直接支持扩大的外侧脑室下区（oSVZ）的发育，进而支持新皮质的扩展。oRG的产生对于模拟和研究人类新皮质发育与扩展的潜在机制至关重要。通过使用在定向皮质类器官中不产生的白血病抑制因子（LIF）激活信号转导和转录激活因子3（STAT3）通路，我们开发了一种从人多能干细胞（hPSC）分化出脑类器官的方法，该方法概括了祖细胞池向oSVZ的扩展。结构化的oSVZ由表达特定oRG标志物（如 ）的祖细胞组成，这与人类oRG 密切匹配。在这种微环境中，皮质神经元表现出更快的成熟，代谢和功能活性增强。将hPSC衍生的产生脑源性血管LIF的周细胞整合到脑类器官中可模拟LIF治疗的效果。这些数据表明，包括脑血管细胞类型在内的皮质微环境的细胞复杂性有利于oRG的出现，并为在hPSC衍生的脑类器官中常规研究oRG提供了一个平台。
