Advances in Cerebral Organoid Systems and their Application in Disease Modeling

Liu, Fangkun; Huang, Jing; Zhang, Jintao; Chen, Jindong; Zeng, Yu; Tang, Yongjian; Liu, Zhixiong

doi:10.1016/j.neuroscience.2018.12.013

Cited by 20 publications

(25 citation statements)

References 72 publications

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“…Although Aβ plays the fundamental role in the pathogenesis of AD, the evolutionary preservation of APP and the existence of APP isoforms that lack the APP gene sequence indicate that amyloid formation is not an intended physiological function of this family of proteins under normal circumstance. Current amassed evidence has shown that APP is vital for the generation, differentiation, and migration of neurons [31]. In dominant expression neuronal cells could rescue this phenotype significantly.…”

Section: Neuronal Roles Of Appmentioning

confidence: 99%

Promising Modulatory Effects of Autophagy on APP Processing as a Potential Treatment for Alzheimer's Disease

Rahman¹,

Rahman²,

Rahman³

et al. 2020

Preprint

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Autophagy refers to the degradation of cytoplasmic constituents by a lysosomal-mediated pathway, which plays a critical role in maintaining cellular homeostasis. Importantly, dysregulation of autophagy has been implicated in multiple neurodegenerative disorders. Previous studies reported that autophagy affects the processing of amyloid precursor protein (APP), thus stimulating β‐amyloid (Aβ) production in Alzheimer’s disease (AD) eventually. Although the mechanism of autophagy modulation on APP processing and its pathogenesis has not yet been fully elucidated at the molecular level, but modulation of autophagy has received considerable attention as a promising approach for the treatment of AD. In the early stage of AD, Aβ may prompt autophagy to facilitate its removal via mTOR‐independent as well as-dependent pathways. However, a recent study proposed that autophagy processes are not properly regulated as AD continues to progress, and consequently, the production of Aβ tends to accumulate rapidly. Meanwhile, a number of autophagy-related genes (Atg) as well as APP genes are also thought to influence the development of AD, which may serve as a bi‐directional link to autophagy and AD pathology. In this review, we summarized current observations related to autophagy regulation and APP processing, focusing on their dynamic modifications associated with the progression of AD. Recent findings together highlight the essential role of autophagy in the removal and clearance of APP and Aβ deposition in the pathological condition of AD.

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Section: Neuronal Roles Of Appmentioning

confidence: 99%

Promising Modulatory Effects of Autophagy on APP Processing as a Potential Treatment for Alzheimer's Disease

Rahman¹,

Rahman²,

Rahman³

et al. 2020

Preprint

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“…An emerging strategy to model human brain development and dysfunction involves the formation of "brain organoids" from iNSCs (4,30,(39)(40)(41)(43)(44)(45). These in vitro miniature brains are developed in 3D and can consist of distinct human brain regions including ventricles, cerebral cortex, hippocampus, hypothalamus, forebrain, midbrain, choroid plexus, and more.…”

Section: Modeling Neuronal Development and Degenerative Diseasesmentioning

confidence: 99%

“…A major limitation of this model, however, is the furthest size and developmental stage that organoids can attain before becoming necrotic. Engineering organoids to contain vasculature will permit further development and maturation in vitro for modeling post-natal brain development and degeneration (45,54).…”

Section: Modeling Neuronal Development and Degenerative Diseasesmentioning

confidence: 99%

From Zero to Neuro-Reprogramming: Innovations in Translational Neuroregenerative Medicine

Galuta

Tsai²

2019

UOJM

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Acquiring live human nervous tissue for research presents ethical and technical constraints. As a result, clinicians and scientists resort to using animal models to investigate human neuronal development and degeneration. However, innate species differences in neurobiology have hindered the translation of disease pathologies and development of therapeutic strategies. The discovery of endogenous neural stem cells (NSCs) and their examination has been critical for neuronal development, degeneration and regeneration. NSCs can exist in different developmental stages, embryonic through adult, and possess the capacity to generate the various cells that make up the nervous system. Importantly, human somatic cells can be obtained non-invasively and genetically reprogrammed into NSCs providing an ethically viable source of stem cells for translational study and potential therapy. Novel methods to generate NSCs of various developmental origins and regional identities are rapidly evolving to provide safer, quicker, and more efficient reprogramming strategies. Reprogrammed NSCs share many molecular and functional attributes with their endogenous NSC counterparts and can be used for in vitro modelling at a large scale. The accessibility to study patient specific NSCs allows the causal inferences of human disease mechanisms that may be unfeasible to model in animals. Despite the novelty of this burgeoning field, the opportunity for translational discoveries in neuronal development and degeneration and for therapeutic applications is unprecedented. This review will highlight the advances in manufacturing NSCs and their translational implications for disease modelling and potential treatment of the nervous system.

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“…Bagley et al (2017) developed the fusion method where both dorsal and ventral forebrain regions were fused into one organoid body with a dorsal-ventral axis [30]. In addition to microcephaly, disease pathogenesis models have been developed for autism spectrum disorder, Sandhoff disease, Miller-Dieker syndrome, and schizophrenia [27,31,32,33,34,35,36,37]. Brain organoids have also been developed for Dengue and ZIKA viral infection [34,38,39].…”

Section: Introduction: the Clinical Need For In Vitro Neural Modelsmentioning

confidence: 99%

“…In vivo, the embryonic brain development is guided by the embryonic body axes which are lacking in vitro. Consistent spatial development has been achieved in organoids, however a large variability in size and tissue structure has limited the generation of disease pathogenesis models [23,24,25,31]. Organoids are restricted to a small size (maximum of several millimeters), due to the lack of nutritional supply to deeper regions [23,24,31,41].…”

Section: Introduction: the Clinical Need For In Vitro Neural Modelsmentioning

confidence: 99%

Layer-By-Layer: The Case for 3D Bioprinting Neurons to Create Patient-Specific Epilepsy Models

2019

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The ability to create three-dimensional (3D) models of brain tissue from patient-derived cells, would open new possibilities in studying the neuropathology of disorders such as epilepsy and schizophrenia. While organoid culture has provided impressive examples of patient-specific models, the generation of organised 3D structures remains a challenge. 3D bioprinting is a rapidly developing technology where living cells, encapsulated in suitable bioink matrices, are printed to form 3D structures. 3D bioprinting may provide the capability to organise neuronal populations in 3D, through layer-by-layer deposition, and thereby recapitulate the complexity of neural tissue. However, printing neuron cells raises particular challenges since the biomaterial environment must be of appropriate softness to allow for the neurite extension, properties which are anathema to building self-supporting 3D structures. Here, we review the topic of 3D bioprinting of neurons, including critical discussions of hardware and bio-ink formulation requirements.

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Advances in Cerebral Organoid Systems and their Application in Disease Modeling

Cited by 20 publications

References 72 publications

Promising Modulatory Effects of Autophagy on APP Processing as a Potential Treatment for Alzheimer's Disease

Promising Modulatory Effects of Autophagy on APP Processing as a Potential Treatment for Alzheimer's Disease

From Zero to Neuro-Reprogramming: Innovations in Translational Neuroregenerative Medicine

Layer-By-Layer: The Case for 3D Bioprinting Neurons to Create Patient-Specific Epilepsy Models

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