Human pluripotent stem cell-derived brain organoids as in vitro models for studying neural disorders and cancer

Abstract

The sheer complexities of brain and resource limitation of human brain tissue greatly hamper our understanding of the brain disorders and cancers. Recently developed three-dimensional (3D) brain organoids (BOs) are self-organized and spontaneously differentiated from human pluripotent stem cells (hPSCs) in vitro, which exhibit similar features with cell type diversity, structural organization, and functional connectivity as the developing human brain. Based on these characteristics, hPSC-derived BOs (hPDBOs) provide new opportunities to recapitulate the complicated processes during brain development, neurodegenerative disorders, and brain cancers in vitro. In this review, we will provide an overview of existing BO models and summarize the applications of this technology in modeling the neural disorders and cancers. Furthermore, we will discuss the challenges associated with their use as in vitro models for disease modeling and the potential future direction.

Keywords: Brain organoids; Cancer; Human pluripotent stem cells; Neural disorders.

Fig. 1

Development of brain organoid technologies: Timeline cartoons to indicate the milestones from isolation of m/hESCs to establishment of mature hPDBOs, including vascularized BOs, region-specific BOs and assembloids

Fig. 2

Challenges of existing hPDBOs: 1. Limited reproducibility: attempt to develop homogenous hPDBOs by introducing new biomaterials or combining with microfabrication techniques; 2. Lack of vascular system: different attempts to realize organoid vascularization, including hPDBOs co-culture with endothelial cells, or co-differentiation with VEGF administration or co-overexpression with hETV2; 3. Deficiency of immune responses: attempt to develop microglia-containing brain organoids by co-culture of hPDBOs with microglial cells

Fig. 3

Future perspectives in hPDBOs: The combinations of hPDBOs and innovative technologies, including cell reprogramming, genome-editing, 3D bioprinting, scRNA-seq, and biomaterials will greatly improve the brain organoid system, and which will facilitate us to model human brain development and disorders, and to perform drug discovery and personalized therapeutics in the future