Interaction between form and fate during human neural development

Genetics instructs on cell differentiation. Controlled cell differentiation over time and space determines the formation of complex tissue structures. Tissue architecture is permissive to tissue function. Little is known about whether tissue architecture influences cell fate acquisition. We sought to investigate the interaction between shape and fate during neural development. We relied on cerebral organoids as a tractable *in vitro* system where tissue shape can be manipulated following several complementary approaches and tissue identity assessed by transcriptomics. We first discovered key protocol variables that contribute to differences in organoid morphology. We designed a pipeline to quality- screen organoids based on their morphological features. Morphology alone can predict organoid cytoarchitecture and transcriptional proximity to the *in vivo* developing brain. Organoids with complex morphology display more and larger ventricles with thicker progenitor layer. They better resemble the transcriptome of foetal brain. Organoids with poor morphology and cytoarchitecture display an aberrant cell repertoire with fewer basal progenitors and upper-layer neurons. They fail to undergo proper developmental trajectories of events. Neurons maintain the signature of progenitors. Progenitors express neuronal genes early on. We observed a similar dysmaturity as in cortical dysplasia. We perturbed cytoarchitecture by mechanical dissociation-reaggregation of the organoid. We achieved a controlled morphology by encapsulating the organoid in hydrogel. Both perturbation paradigms resulted in aberrant cytoarchitecture and cells with a poised neuron/progenitor identity. We demonstrated that cell positioning influences cell fate. Next, we showed neural network dynamics in mature organoids. Organoids with poor morphology display isotropic neural networks. Overall, we demonstrated how shape influences fate during neural development.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2023

Author dc:creator

• Chiaradia, Ilaria

Advisor dc:contributor.advisor

• Lancaster, Madeline A

• brain
• development
• human
• morphology
• nervous system
• organoids
• shape
• stem cells
• tissue fate
• transcriptome

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/ba951380-f562-4539-bdaf-e96ed7963f6c/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.106005

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/364265