Purpose of review

Applying discoveries from basic research to patients in the neonatal intensive care unit (NICU) is challenging given the difficulty of modeling this population in animal models, lack of translational relevance from animal models to humans, and scarcity of primary human tissue. Human cell-derived cerebral organoid models are an appealing way to address some of these gaps. In this review, we will touch on previous work to model neonatal conditions in cerebral organoids, some limitations of this approach, and recent strategies that have attempted to address these limitations.

Recent findings

While modeling of neurodevelopmental disorders has been an application of cerebral organoids since their initial description, recent studies have dramatically expanded the types of brain regions and disease models available. Additionally, work to increase the complexity of organoid models by including immune and vascular cells, as well as modeling human heterogeneity with mixed donor organoids will provide new opportunities to model neonatal pathologies.

Summary

Organoids are an attractive model to study human neurodevelopmental pathologies relevant to patients in the neonatal ICU. New technologies will broaden the applicability of these models to neonatal research and their usefulness as a drug screening platform.

Interactions between angiogenesis and neurogenesis regulate embryonic brain development. However, a comprehensive understanding of the stages of vascular cell maturation is lacking, especially in the prenatal human brain. Using fluorescence-activated cell sorting, single-cell transcriptomics, and histological and ultrastructural analyses, we show that an ensemble of endothelial and mural cell subtypes tile the brain vasculature during the second trimester. These vascular cells follow distinct developmental trajectories and utilize diverse signaling mechanisms, including collagen, laminin, and midkine, to facilitate cell-cell communication and maturation. Interestingly, our results reveal that tip cells, a subtype of endothelial cells, are highly enriched near the ventricular zone, the site of active neurogenesis. Consistent with these observations, prenatal vascular cells transplanted into cortical organoids exhibit restricted lineage potential that favors tip cells, promotes neurogenesis, and reduces cellular stress. Together, our results uncover important mechanisms into vascular maturation during this critical period of human brain development.