iPSC-derived three-dimensional brain organoid models and neurotropic viral infections

Abstract

Progress in stem cell research has revolutionized the medical field for more than two decades. More recently, the discovery of induced pluripotent stem cells (iPSCs) has allowed for the development of advanced disease modeling and tissue engineering platforms. iPSCs are generated from adult somatic cells by reprogramming them into an embryonic-like state via the expression of transcription factors required for establishing pluripotency. In the context of the central nervous system (CNS), iPSCs have the potential to differentiate into a wide variety of brain cell types including neurons, astrocytes, microglial cells, endothelial cells, and oligodendrocytes. iPSCs can be used to generate brain organoids by using a constructive approach in three-dimensional (3D) culture in vitro. Recent advances in 3D brain organoid modeling have provided access to a better understanding of cell-to-cell interactions in disease progression, particularly with neurotropic viral infections. Neurotropic viral infections have been difficult to study in two-dimensional culture systems in vitro due to the lack of a multicellular composition of CNS cell networks. In recent years, 3D brain organoids have been preferred for modeling neurotropic viral diseases and have provided invaluable information for better understanding the molecular regulation of viral infection and cellular responses. Here we provide a comprehensive review of the literature on recent advances in iPSC-derived 3D brain organoid culturing and their utilization in modeling major neurotropic viral infections including HIV-1, HSV-1, JCV, ZIKV, CMV, and SARS-CoV2.

Keywords: 3D organoids; CMV; HIV-1; HSV-1; JCV; Latency; Neurotropic viruses; SARS-CoV-2; ZIKV.

Fig. 1

Differentiation of different types of human brain organoids from stem cell–derived embryoid bodies using either guided or unguided maturation protocols, as well as assembloid formation (created with biorender.com). Cerebral organoids were stained with H&E and neurons, microglia, astrocytes, and oligodendrocytes were visualized by immunohistochemistry (IHC) TUJ-1/MAP2, IBA1, GFAP, and Olig2 specific antibodies, respectively