Maturation and circuit integration of transplanted human cortical organoids

Omer Revah, Felicity Gore, Kevin W. Kelley, Jimena Andersen, Noriaki Sakai, Xiaoyu Chen, Min-Yin Li, Fikri Birey, Xiao Yang, Nay L. Saw, Samuel W. Baker, Neal D. Amin, Shravanti Kulkarni, Rachana Mudipalli, Bianxiao Cui, Seiji Nishino, Gerald A. Grant, Juliet K. Knowles, Mehrdad Shamloo, John R. Huguenard, Karl Deisseroth and Sergiu P. Pașca ()
Additional contact information
Omer Revah: Stanford University
Felicity Gore: Stanford University
Kevin W. Kelley: Stanford University
Jimena Andersen: Stanford University
Noriaki Sakai: Stanford University
Xiaoyu Chen: Stanford University
Min-Yin Li: Stanford University
Fikri Birey: Stanford University
Xiao Yang: Stanford University
Nay L. Saw: Stanford University
Samuel W. Baker: Stanford University
Neal D. Amin: Stanford University
Shravanti Kulkarni: Stanford University
Rachana Mudipalli: Stanford University
Bianxiao Cui: Stanford University
Seiji Nishino: Stanford University
Gerald A. Grant: Stanford University
Juliet K. Knowles: Department of Neurology and Neurological Sciences
Mehrdad Shamloo: Stanford University
John R. Huguenard: Department of Neurology and Neurological Sciences
Karl Deisseroth: Stanford University
Sergiu P. Pașca: Stanford University

Nature, 2022, vol. 610, issue 7931, 319-326

Abstract: Abstract Self-organizing neural organoids represent a promising in vitro platform with which to model human development and disease1–5. However, organoids lack the connectivity that exists in vivo, which limits maturation and makes integration with other circuits that control behaviour impossible. Here we show that human stem cell-derived cortical organoids transplanted into the somatosensory cortex of newborn athymic rats develop mature cell types that integrate into sensory and motivation-related circuits. MRI reveals post-transplantation organoid growth across multiple stem cell lines and animals, whereas single-nucleus profiling shows progression of corticogenesis and the emergence of activity-dependent transcriptional programs. Indeed, transplanted cortical neurons display more complex morphological, synaptic and intrinsic membrane properties than their in vitro counterparts, which enables the discovery of defects in neurons derived from individuals with Timothy syndrome. Anatomical and functional tracings show that transplanted organoids receive thalamocortical and corticocortical inputs, and in vivo recordings of neural activity demonstrate that these inputs can produce sensory responses in human cells. Finally, cortical organoids extend axons throughout the rat brain and their optogenetic activation can drive reward-seeking behaviour. Thus, transplanted human cortical neurons mature and engage host circuits that control behaviour. We anticipate that this approach will be useful for detecting circuit-level phenotypes in patient-derived cells that cannot otherwise be uncovered.

Date: 2022
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DOI: 10.1038/s41586-022-05277-w

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