Advances in neural organoid systems and their application in neurotoxicity testing of environmental chemicals

Yuanyuan Zheng,Fangrong Zhang,Shengmin Xu,Lijun Wu

doi:10.1186/s41021-021-00214-1

Abstract

Due to the complex structure and function of central nervous system (CNS), human CNS in vitro modeling is still a great challenge. Neurotoxicity testing of environmental chemicals mainly depends on the traditional animal models, which have various limitations such as species differences, expensive and time-consuming. Meanwhile, in vitro two-dimensional (2D) cultured cells or three-dimensional (3D) cultured neurospheres cannot fully simulate complex 3D structure of neural tissues. Recent advancements in neural organoid systems provides excellent models for the testing of environmental chemicals that affect the development of human CNS. Neural organoids derived from hPSCs not only can simulate the process of CNS development, including early stage neural tube formation, neuroepithelium differentiation and regional specification, but also its 3D structure, thus can be used to evaluate the effect of chemicals on differentiation and morphogenesis. Here, we provide a review of recent progress in the methods of culturing neural organoids and their applications in neurotoxicity testing of environmental chemicals. We conclude by highlighting challenge and future directions in neurotoxicity testing based on neural organoids.

Highlights

If fetus exposed to industrial chemicals in the environment, the development of central nervous system (CNS) might be damaged, and neurodevelopmental disorders and birth defects will occur, such as attention deficit hyperactivity disorder (ADHD), mental retardation and neural tube defects
It reported that new environmental chemicals such as perfluorinated compounds and bisphenol compounds have been detected in pregnant women [8]
The results showed that Bisphenol A (BPA) led to a dose-dependent decrease in the relative VZ thickness of forebrain organoids after treating with BPA from days 14 to 28

Summary

Background

If fetus exposed to industrial chemicals in the environment, the development of central nervous system (CNS) might be damaged, and neurodevelopmental disorders and birth defects will occur, such as attention deficit hyperactivity disorder (ADHD), mental retardation and neural tube defects. Xuyu Qian and colleagues developed a low-cost, easy-to-operate, miniaturized spinning bioreactor (SpinΩ) for brain organoids culture through 3D printing technology [38] By this device, various region-specific organoids have been successfully developed, for example the forebrain, midbrain, and hypothalamus via the addition of specific patterning factors, further advancing in vitro method for neurotoxicity testing assessment of chemicals. Zheng et al developed a human neural tube model, which could develop into dorsal ventral patterned spinal cord organoid from hPSCs based on a Gel3D culture system (Fig. 2A) [46]. This culture system integrated some key neurogenic niche elements in vivo, including a 3D basement membrane ECM and a soft gel bed, to reconstruct the mechanical microenvironment of neuroepithelium during neurogenesis. The brain organoids they developed are the first 3D model including blood vessels

Limitations

Conclusions