Engineered extracellular matrices facilitate brain organoids from human pluripotent stem cells

Abstract

Objective Brain organoids are miniaturized in vitro brain models generated from pluripotent stem cells, which resemble full‐sized brain more closely than conventional two‐dimensional cell cultures. Although brain organoids mimic the human brain's cell‐to‐cell network interactions, they generally fail to faithfully recapitulate cell‐to‐matrix interactions. Here, an engineered framework, called an engineered extracellular matrix (EECM), was developed to provide support and cell‐to‐matrix interactions to developing brain organoids. Methods We generated brain organoids using EECMs comprised of human fibrillar fibronectin supported by a highly porous polymer scaffold. The resultant brain organoids were characterized by immunofluorescence microscopy, transcriptomics, and proteomics of the cerebrospinal fluid (CSF) compartment. Results The interstitial matrix‐mimicking EECM enhanced neurogenesis, glial maturation, and neuronal diversity from human embryonic stem cells versus conventional protein matrix (Matrigel). Additionally, EECMs supported long‐term culture, which promoted large‐volume organoids containing over 250 μL of CSF. Proteomics analysis of the CSF found it superseded previous brain organoids in protein diversity, as indicated by 280 proteins spanning 500 gene ontology pathways shared with adult CSF. Interpretation Engineered EECM matrices represent a major advancement in neural engineering as they have the potential to significantly enhance the structural, cellular, and functional diversity that can be achieved in advanced brain models.

Development of brain organoid technology derived from iPSC for the neurodegenerative disease modelling: a glance through

“…The brain organoids offer new systems that can overcome most of the hindrances and are constantly refined progressively. The self-organization of brain organoids in a three-dimensional environment may efficiently mimic human brain architecture and functions, such as differentiation ( García-Delgado et al, 2022 ), mediate synaptic functions for brain circuitry development ( Yakoub and Sadek, 2019 ) neuronal cell migration ( Saglam-Metiner et al, 2023 ), and human-specific cell–cell and cell–matrix interactions ( Muñiz et al, 2023 ) which facilitates human brain developmental morphogenesis. Thus, brain organoids may shed light on the process of neural tissue development and differentiation.…”