Generation of Functional Human 3D Cortico-Motor Assembloids

assembloids;类组装体; cerebral cortex;大脑皮层; connectivity;连通性; corticospinal;皮质脊髓; human pluripotent stem cells;人类多能干细胞; neuromuscular;神经肌肉; optogenetics;光遗传学; organoids;类器官; rabies tracing;狂犬病追踪; spinal cord;脊髓

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Philipp Georg, Rosario Astaburuaga-García, Lorenzo Bonaguro, Sophia Brumhard, Laura Michalick, Lena J Lippert, Tomislav Kostevc, Christiane Gäbel, Maria Schneider, Mathias Streitz, Vadim Demichev, Ioanna Gemünd, Matthias Barone, Pinkus Tober-Lau, Elisa T Helbig, David Hillus, Lev Petrov, Julia Stein, Hannah-Philine Dey, Daniela Paclik, Christina Iwert, Michael Mülleder, Simran Kaur Aulakh, Sonja Djudjaj, Roman D Bülow, Henrik E Mei, Axel R Schulz, Andreas Thiel, Stefan Hippenstiel, Antoine-Emmanuel Saliba, Roland Eils, Irina Lehmann, Marcus A Mall, Sebastian Stricker, Jobst Röhmel, Victor M Corman, Dieter Beule, Emanuel Wyler, Markus Landthaler, Benedikt Obermayer, Saskia von Stillfried, Peter Boor, Münevver Demir, Hans Wesselmann, Norbert Suttorp, Alexander Uhrig, Holger Müller-Redetzky, Jacob Nattermann, Wolfgang M Kuebler, Christian Meisel, Markus Ralser, Joachim L Schultze, Anna C Aschenbrenner, Charlotte Thibeault, Florian Kurth, Leif E Sander, Nils Blüthgen, Birgit Sawitzki; PA-COVID-19 Study Group

期刊 Cell
时间 2022
起止号 185(3):493-512.e25.
种属 Human
技术平台单细胞测序
样本类型 blood cells
研究方向神经系统
细胞类型其它细胞

Abstract

Neurons in the cerebral cortex connect through descending pathways to hindbrain and spinal cord to activate muscle and generate movement. Although components of this pathway have been previously generated and studied in vitro, the assembly of this multi-synaptic circuit has not yet been achieved with human cells. Here, we derive organoids resembling the cerebral cortex or the hindbrain/spinal cord and assemble them with human skeletal muscle spheroids to generate 3D cortico-motor assembloids. Using rabies tracing, calcium imaging, and patch-clamp recordings, we show that corticofugal neurons project and connect with spinal spheroids, while spinal-derived motor neurons connect with muscle. Glutamate uncaging or optogenetic stimulation of cortical spheroids triggers robust contraction of 3D muscle, and assembloids are morphologically and functionally intact for up to 10 weeks post-fusion. Together, this system highlights the remarkable self-assembly capacity of 3D cultures to form functional circuits that could be used to understand development and disease.

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Abstract

Abstract