Challenges of Organoid Research

Abstract

Organoids are 3D cell culture systems derived from human pluripotent stem cells that contain tissue resident cell types and reflect features of early tissue organization. Neural organoids are a particularly innovative scientific advance given the lack of accessibility of developing human brain tissue and intractability of neurological diseases. Neural organoids have become an invaluable approach to model features of human brain development that are not well reflected in animal models. Organoids also hold promise for the study of atypical cellular, molecular, and genetic features that underscore neurological diseases. Additionally, organoids may provide a platform for testing therapeutics in human cells and are a potential source for cell replacement approaches to brain injury or disease. Despite the promising features of organoids, their broad utility is tempered by a variety of limitations yet to be overcome, including lack of high-fidelity cell types, limited maturation, atypical physiology, and lack of arealization, features that may limit their reliability for certain applications.

Keywords: human development; modeling human disease; neural development; neuroscience; organoids; stem cell models.

Figure 1

Features of cerebral organoids. Organoids robustly replicate proliferation and division programs and spontaneously organize into a rudimentary radial scaffold. Neural progenitors generate neurons and later differentiate into astroglial cells. However, cerebral organoids still require validation for certain applications and continued refinement to better replicate neurodevelopmental features. Currently, organoids are impaired in gene expression programs that define robust cell type specification. They lack specific nonneural cell types that are vital for brain health and function, including vascular endothelial and mural cells and immune microglia. Organoids also may not replicate complex physiological dynamics that define intracortical and subcortical circuitry. Figure adapted from Bhaduri et al. (2020a).