Oh Yohan, Cho Gun-Sik, Li Zhe, Hong Ingie, Zhu Renjun, Kim Min-Jeong, Kim Yong Jun, Tampakakis Emmanouil, Tung Leslie, Huganir Richard, Dong Xinzhong, Kwon Chulan, Lee Gabsang
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130, USA.
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Cell Stem Cell. 2016 Jul 7;19(1):95-106. doi: 10.1016/j.stem.2016.05.002. Epub 2016 Jun 16.
Neurons derived from human pluripotent stem cells (hPSCs) are powerful tools for studying human neural development and diseases. Robust functional coupling of hPSC-derived neurons with target tissues in vitro is essential for modeling intercellular physiology in a dish and to further translational studies, but it has proven difficult to achieve. Here, we derive sympathetic neurons from hPSCs and show that they can form physical and functional connections with cardiac muscle cells. Using multiple hPSC reporter lines, we recapitulated human autonomic neuron development in vitro and successfully isolated PHOX2B::eGFP+ neurons that exhibit sympathetic marker expression and electrophysiological properties and norepinephrine secretion. Upon pharmacologic and optogenetic manipulation, PHOX2B::eGFP+ neurons controlled beating rates of cardiomyocytes, and the physical interactions between these cells increased neuronal maturation. This study provides a foundation for human sympathetic neuron specification and for hPSC-based neuronal control of organs in a dish.
源自人类多能干细胞（hPSC）的神经元是研究人类神经发育和疾病的有力工具。hPSC衍生神经元与体外靶组织的强大功能耦合对于在培养皿中模拟细胞间生理学以及进一步的转化研究至关重要，但事实证明这很难实现。在这里，我们从hPSC中衍生出交感神经元，并表明它们可以与心肌细胞形成物理和功能连接。使用多个hPSC报告系，我们在体外重现了人类自主神经元的发育，并成功分离出表现出交感神经标记物表达、电生理特性和去甲肾上腺素分泌的PHOX2B::eGFP+神经元。经过药理学和光遗传学操作后，PHOX2B::eGFP+神经元控制着心肌细胞的跳动频率，并且这些细胞之间的物理相互作用促进了神经元的成熟。这项研究为人类交感神经元的特化以及基于hPSC的体外器官神经元控制奠定了基础。
