Center for Stem Cell Biology and Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Institute of Oncology Research (IOR), Bellinzona Institutes of Science (BIOS+), 6500 Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera Italiana, 6900 Lugano, Switzerland.
Cell Rep. 2024 Apr 23;43(4):114031. doi: 10.1016/j.celrep.2024.114031. Epub 2024 Apr 6.
Outer radial glia (oRG) emerge as cortical progenitor cells that support the development of an enlarged outer subventricular zone (oSVZ) and the expansion of the neocortex. The in vitro generation of oRG is essential to investigate the underlying mechanisms of human neocortical development and expansion. By activating the STAT3 signaling pathway using leukemia inhibitory factor (LIF), which is not expressed in guided cortical organoids, we define a cortical organoid differentiation method from human pluripotent stem cells (hPSCs) that recapitulates the expansion of a progenitor pool into the oSVZ. The oSVZ comprises progenitor cells expressing specific oRG markers such as GFAP, LIFR, and HOPX, closely matching human fetal oRG. Finally, incorporating neural crest-derived LIF-producing cortical pericytes into cortical organoids recapitulates the effects of LIF treatment. These data indicate that increasing the cellular complexity of the organoid microenvironment promotes the emergence of oRG and supports a platform to study oRG in hPSC-derived brain organoids routinely.
外放射状胶质细胞（oRG）作为皮质祖细胞出现，支持扩大的外侧室下区（oSVZ）和新皮层的扩张。体外产生 oRG 对于研究人类新皮层发育和扩张的潜在机制至关重要。通过使用白血病抑制因子（LIF）激活 STAT3 信号通路，该因子在定向皮质类器官中不表达，我们定义了一种从人类多能干细胞（hPSC）分化为皮质类器官的方法，该方法可将祖细胞池扩增到 oSVZ。oSVZ 包含表达特定 oRG 标志物的祖细胞，如 GFAP、LIFR 和 HOPX，与人类胎儿 oRG 非常匹配。最后，将神经嵴衍生的产生 LIF 的皮质周细胞纳入皮质类器官中，重现了 LIF 处理的效果。这些数据表明，增加类器官微环境的细胞复杂性可促进 oRG 的出现，并支持在 hPSC 衍生的脑类器官中常规研究 oRG 的平台。
