Temporal morphogen gradient-driven neural induction shapes single expanded neuroepithelium brain organoids with enhanced cortical identity

Anna Pagliaro, Roxy Finger, Iris Zoutendijk, Saskia Bunschuh, Hans Clevers, Delilah Hendriks () and Benedetta Artegiani ()
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Anna Pagliaro: The Princess Maxima Center for Pediatric Oncology
Roxy Finger: The Princess Maxima Center for Pediatric Oncology
Iris Zoutendijk: The Princess Maxima Center for Pediatric Oncology
Saskia Bunschuh: The Princess Maxima Center for Pediatric Oncology
Hans Clevers: The Princess Maxima Center for Pediatric Oncology
Delilah Hendriks: The Princess Maxima Center for Pediatric Oncology
Benedetta Artegiani: The Princess Maxima Center for Pediatric Oncology

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Pluripotent stem cell (PSC)-derived human brain organoids enable the study of human brain development in vitro. Typically, the fate of PSCs is guided into subsequent specification steps through static medium switches. In vivo, morphogen gradients are critical for proper brain development and determine cell specification, and associated defects result in neurodevelopmental disorders. Here, we show that initiating neural induction in a temporal stepwise gradient guides the generation of brain organoids composed of a single, self-organized apical-out neuroepithelium, termed ENOs (expanded neuroepithelium organoids). This is at odds with standard brain organoid protocols in which multiple and independent neuroepithelium units (rosettes) are formed. We find that a prolonged, decreasing gradient of TGF-β signaling is a determining factor in ENO formation and allows for an extended phase of neuroepithelium expansion. In-depth characterization reveals that ENOs display improved cellular morphology and tissue architectural features that resemble in vivo human brain development, including expanded germinal zones. Consequently, cortical specification is enhanced in ENOs. ENOs constitute a platform to study the early events of human cortical development and allow interrogation of the complex relationship between tissue architecture and cellular states in shaping the developing human brain.

Date: 2023
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DOI: 10.1038/s41467-023-43141-1

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