A patterned human neural tube model using microfluidic gradients

Xufeng Xue, Yung Su Kim, Alfredo-Isaac Ponce-Arias, Richard O’Laughlin, Robin Zhexuan Yan, Norio Kobayashi, Rami Yair Tshuva, Yu-Hwai Tsai, Shiyu Sun, Yi Zheng, Yue Liu, Frederick C. K. Wong, Azim Surani, Jason R. Spence, Hongjun Song, Guo-Li Ming, Orly Reiner and Jianping Fu ()
Additional contact information
Xufeng Xue: University of Michigan
Yung Su Kim: University of Michigan
Alfredo-Isaac Ponce-Arias: Weizmann Institute of Science
Richard O’Laughlin: Weizmann Institute of Science
Robin Zhexuan Yan: University of Michigan
Norio Kobayashi: University of Michigan
Rami Yair Tshuva: Weizmann Institute of Science
Yu-Hwai Tsai: University of Michigan Medical School
Shiyu Sun: University of Michigan
Yi Zheng: University of Michigan
Yue Liu: University of Michigan
Frederick C. K. Wong: University of Cambridge
Azim Surani: University of Cambridge
Jason R. Spence: University of Michigan Medical School
Hongjun Song: University of Pennsylvania
Guo-Li Ming: University of Pennsylvania
Orly Reiner: Weizmann Institute of Science
Jianping Fu: University of Michigan

Nature, 2024, vol. 628, issue 8007, 391-399

Abstract: Abstract The human nervous system is a highly complex but organized organ. The foundation of its complexity and organization is laid down during regional patterning of the neural tube, the embryonic precursor to the human nervous system. Historically, studies of neural tube patterning have relied on animal models to uncover underlying principles. Recently, models of neurodevelopment based on human pluripotent stem cells, including neural organoids1–5 and bioengineered neural tube development models6–10, have emerged. However, such models fail to recapitulate neural patterning along both rostral–caudal and dorsal–ventral axes in a three-dimensional tubular geometry, a hallmark of neural tube development. Here we report a human pluripotent stem cell-based, microfluidic neural tube-like structure, the development of which recapitulates several crucial aspects of neural patterning in brain and spinal cord regions and along rostral–caudal and dorsal–ventral axes. This structure was utilized for studying neuronal lineage development, which revealed pre-patterning of axial identities of neural crest progenitors and functional roles of neuromesodermal progenitors and the caudal gene CDX2 in spinal cord and trunk neural crest development. We further developed dorsal–ventral patterned microfluidic forebrain-like structures with spatially segregated dorsal and ventral regions and layered apicobasal cellular organizations that mimic development of the human forebrain pallium and subpallium, respectively. Together, these microfluidics-based neurodevelopment models provide three-dimensional lumenal tissue architectures with in vivo-like spatiotemporal cell differentiation and organization, which will facilitate the study of human neurodevelopment and disease.

Date: 2024
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DOI: 10.1038/s41586-024-07204-7

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