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Tissue morphology influences the temporal program of human brain organoid development.

ABSTRACT: Progression through fate decisions determines cellular composition and tissue architecture, but how that same architecture may impact cell fate is less clear. We took advantage of organoids as a tractable model to interrogate this interaction of form and fate. Screening methodological variations revealed that common protocol adjustments impacted various aspects of morphology, from macrostructure to tissue architecture. We examined the impact of morphological perturbations on cell fate through integrated single nuclear RNA sequencing (snRNA-seq) and spatial transcriptomics. Regardless of the specific protocol, organoids with more complex morphology better mimicked in vivo human fetal brain development. Organoids with perturbed tissue architecture displayed aberrant temporal progression, with cells being intermingled in both space and time. Finally, encapsulation to impart a simplified morphology led to disrupted tissue cytoarchitecture and a similar abnormal maturational timing. These data demonstrate that cells of the developing brain require proper spatial coordinates to undergo correct temporal progression.

SUBMITTER: Chiaradia I

PROVIDER: S-EPMC10765088 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Tissue morphology influences the temporal program of human brain organoid development.

Chiaradia Ilaria I Imaz-Rosshandler Ivan I Nilges Benedikt S BS Boulanger Jerome J Pellegrini Laura L Das Richa R Kashikar Nachiket D ND Lancaster Madeline A MA

Cell stem cell 20231001 10

Progression through fate decisions determines cellular composition and tissue architecture, but how that same architecture may impact cell fate is less clear. We took advantage of organoids as a tractable model to interrogate this interaction of form and fate. Screening methodological variations revealed that common protocol adjustments impacted various aspects of morphology, from macrostructure to tissue architecture. We examined the impact of morphological perturbations on cell fate through in ...[more]

PMID: 37802039

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Project description:Organs are the ensemble of different cell types in a complex architectural milieu. It is well-known that progression through fate decisions sets up the complex cellular makeup and architecture of an organ, but how that same architecture may impact on cell fate is less clear. We sought to examine this by taking advantage of the unique capabilities of organoids as a tractable in vitro model to interrogate how fate and form interact during organ development. Screening methodological variations encountered in the literature revealed that common protocol adjustments, such as small molecule patterning and exposure to exogenous extracellular matrix, impacted various aspects of morphology, from macro structure to tissue architecture. We demonstrated that overall morphology is a predictor of tissue architecture and that perturbing morphology results in changes in cytoarchitecture. Vice-versa, perturbing cytoarchitecture by mechanically redistributing cells in a random spatial conformation resulted in a simplified overall morphology. We next examined the impact of these morphological perturbations on cell fate through integrated snRNA-seq and spatial transcriptomics within the phenotypic landscape. Regardless of the specific protocol, organoids with more complex morphology better mimicked in vivo human fetal brain development than organoids with simplified morphology. Further, organoids with perturbed tissue architecture profiled with scRNA-seq over a time course experiment displayed aberrant temporal progression in cell fate, with cells being intermingled in both space and time. Finally, imparting a simplified morphology through physical encapsulation led to disrupted tissue cytoarchitecture and a similar abnormal temporal progression. These data not only point to the importance of tissue morphology in organoid fidelity compared to in vivo, but also demonstrate that cells require proper spatial coordinates in order to undergo the proper temporal trajectory of events.

Project description:ObjectiveGenes implicated in schizophrenia are enriched in networks differentially regulated during human CNS development. Neuregulin 3 (NRG3), a brain-enriched neurotrophin, undergoes alternative splicing and is implicated in several neurological disorders with developmental origins. Isoform-specific increases in NRG3 are observed in schizophrenia and associated with rs10748842, a NRG3 risk polymorphism, suggesting NRG3 transcriptional dysregulation as a molecular mechanism of risk. The authors quantitatively mapped the temporal trajectories of NRG3 isoforms (classes I-IV) in the neocortex throughout the human lifespan, examined whether tissue-specific regulation of NRG3 occurs in humans, and determined if abnormalities in NRG3 transcriptomics occur in mood disorders and are genetically determined.MethodNRG3 isoform classes I-IV were quantified using quantitative real-time polymerase chain reaction in human postmortem dorsolateral prefrontal cortex from 286 nonpsychiatric control individuals, from gestational week 14 to 85 years old, and individuals diagnosed with either bipolar disorder (N=34) or major depressive disorder (N=69). Tissue-specific mapping was investigated in several human tissues. rs10748842 was genotyped in individuals with mood disorders, and association with NRG3 isoform expression examined.ResultsNRG3 classes displayed individually specific expression trajectories across human neocortical development and aging; classes I, II, and IV were significantly associated with developmental stage. NRG3 class I was increased in bipolar and major depressive disorder, consistent with observations in schizophrenia. NRG3 class II was increased in bipolar disorder, and class III was increased in major depression. The rs10748842 risk genotype predicted elevated class II and III expression, consistent with previous reports in the brain, with tissue-specific analyses suggesting that classes II and III are brain-specific isoforms of NRG3.ConclusionsMapping the temporal expression of genes during human brain development provides vital insight into gene function and identifies critical sensitive periods whereby genetic factors may influence risk for psychiatric disease. Here the authors provide comprehensive insight into the transcriptional landscape of the psychiatric risk gene, NRG3, in human neocortical development and expand on previous findings in schizophrenia to identify increased expression of developmentally and genetically regulated isoforms in the brain of patients with mood disorders. Principally, the finding that NRG3 classes II and III are brain-specific isoforms predicted by rs10748842 risk genotype and are increased in mood disorders further implicates a molecular mechanism of psychiatric risk at the NRG3 locus and identifies a potential developmental role for NRG3 in bipolar disorder and major depression. These observations encourage investigation of the neurobiology of NRG3 isoforms and highlight inhibition of NRG3 signaling as a potential target for psychiatric treatment development.

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Tissue morphology influences the temporal program of human brain organoid development.

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Tissue morphology influences the temporal program of human brain organoid development.

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