Generation of vascularized brain organoids to study neurovascular interactions

Sun, Xin-Yao; Ju, Xiang-Chun; Li, Yang; Zeng, Peng-Ming; Wu, Jian; Zhou, Yingying; Shen, Libing; Dong, Jian; Chen, Yuejun; Luo, Zhen-Ge

doi:10.7554/elife.76707

Cited by 182 publications

(94 citation statements)

References 77 publications

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“…Similarly, most cell types that form the cerebrovasculature [ 111 ] do not arise from neural stem cells but can be introduced into organoids by co-culture [ 112 , 113 , 114 ] or by ectopic expression of the ETV2 transcription factor [ 115 ] ( Figure 1 d). Endothelial cells can self-organize to form tubular structures reminiscent of early developing vascular networks and can improve the viability of organoid cells and enhance functional maturation [ 115 ].…”

Section: Reducing Stressmentioning

confidence: 99%

Cerebral Organoids as an Experimental Platform for Human Neurogenomics

Nowakowski

Salama

2022

Cells

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The cerebral cortex forms early in development according to a series of heritable neurodevelopmental instructions. Despite deep evolutionary conservation of the cerebral cortex and its foundational six-layered architecture, significant variations in cortical size and folding can be found across mammals, including a disproportionate expansion of the prefrontal cortex in humans. Yet our mechanistic understanding of neurodevelopmental processes is derived overwhelmingly from rodent models, which fail to capture many human-enriched features of cortical development. With the advent of pluripotent stem cells and technologies for differentiating three-dimensional cultures of neural tissue in vitro, cerebral organoids have emerged as an experimental platform that recapitulates several hallmarks of human brain development. In this review, we discuss the merits and limitations of cerebral organoids as experimental models of the developing human brain. We highlight innovations in technology development that seek to increase its fidelity to brain development in vivo and discuss recent efforts to use cerebral organoids to study regeneration and brain evolution as well as to develop neurological and neuropsychiatric disease models.

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Section: Reducing Stressmentioning

confidence: 99%

Cerebral Organoids as an Experimental Platform for Human Neurogenomics

Nowakowski

Salama

2022

Cells

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“…Increased number of neural progenitors, functional BBB-like structures, and active microglial cells were observed in the fused/vascularized brain organoids. Therefore, the fused organoids enable us to investigate interactions between immune and non-immune cells as well as neuronal and non-neuronal cells in vitro [ 100 ]. Thus, these two strategies could serve as a better tool to simulate brain development and model neurological disorders.…”

Section: Future Perspectivesmentioning

confidence: 99%

“…Ao et al developed a simple and versatile acoustofluidic method to partially overcome these disadvantages by a controllable spatial arrangement of organoids [ 111 ]. Recently, a breakthrough was made in the generation of engineered brain-spinal cord assembloids (eBSA) by co-culturing cerebral organoids (COs) and motor neuron spheroids (MNSs) [ 100 ]. The eBSA connects COs and MNSs to recapitulate the brain-spinal cord connection.…”

Section: Future Perspectivesmentioning

confidence: 99%

Human Brain Organoid: A Versatile Tool for Modeling Neurodegeneration Diseases and for Drug Screening

Seong

et al. 2022

Stem Cells International

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Clinical trials serve as the fundamental prerequisite for clinical therapy of human disease, which is primarily based on biomedical studies in animal models. Undoubtedly, animal models have made a significant contribution to gaining insight into the developmental and pathophysiological understanding of human diseases. However, none of the existing animal models could efficiently simulate the development of human organs and systems due to a lack of spatial information; the discrepancy in genetic, anatomic, and physiological basis between animals and humans limits detailed investigation. Therefore, the translational efficiency of the research outcomes in clinical applications was significantly weakened, especially for some complex, chronic, and intractable diseases. For example, the clinical trials for human fragile X syndrome (FXS) solely based on animal models have failed such as mGluR5 antagonists. To mimic the development of human organs more faithfully and efficiently translate in vitro biomedical studies to clinical trials, extensive attention to organoids derived from stem cells contributes to a deeper understanding of this research. The organoids are a miniaturized version of an organ generated in vitro, partially recapitulating key features of human organ development. As such, the organoids open a novel avenue for in vitro models of human disease, advantageous over the existing animal models. The invention of organoids has brought an innovative breakthrough in regeneration medicine. The organoid-derived human tissues or organs could potentially function as invaluable platforms for biomedical studies, pathological investigation of human diseases, and drug screening. Importantly, the study of regeneration medicine and the development of therapeutic strategies for human diseases could be conducted in a dish, facilitating in vitro analysis and experimentation. Thus far, the pilot breakthrough has been made in the generation of numerous types of organoids representing different human organs. Most of these human organoids have been employed for in vitro biomedical study and drug screening. However, the efficiency and quality of the organoids in recapitulating the development of human organs have been hindered by engineering and conceptual challenges. The efficiency and quality of the organoids are essential for downstream applications. In this article, we highlight the application in the modeling of human neurodegenerative diseases (NDDs) such as FXS, Alzheimer’s disease (AD), Parkinson’s disease (PD), and autistic spectrum disorders (ASD), and organoid-based drug screening. Additionally, challenges and weaknesses especially for limits of the brain organoid models in modeling late onset NDDs such as AD and PD., and future perspectives regarding human brain organoids are addressed.

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“…Although each method has its limitations, all aim to incorporate a single type of non-neural cells into brain organoids. Now, in eLife, Zhen-Ge Luo from ShanghaiTech University, Xiang-Chun Ju from the Chinese Academy of Sciences, and co-workers – including Xin-Yao Sun as first author – report on the generation of fusion vessel brain organoids (fVBOrs) with both vascular- and microglia-like cells obtained by fusing vessel organoids with brain organoids ( Sun et al, 2022 ).…”

mentioning

confidence: 99%