Translational potential of human brain organoids

Sun, Alfred Xuyang; Ng, Huck‐Hui; Tan, Eng‐King

doi:10.1002/acn3.505

Cited by 36 publications

(25 citation statements)

References 80 publications

(161 reference statements)

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“…Miniature organ‐like structures that are differentiated from stem cells and mimic in vivo tissues are increasingly of interest, as they may facilitate an improved understanding of human biology and diseases . To date, most brain‐ or midbrain‐like organoids and similar structures have been differentiated from induced pluripotent stem cells (iPSCs) via chemical and genetic manipulation .…”

Section: Introductionmentioning

confidence: 99%

Extracellular Nanomatrix‐Induced Self‐Organization of Neural Stem Cells into Miniature Substantia Nigra‐Like Structures with Therapeutic Effects on Parkinsonian Rats

et al. 2019

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Substantia nigra (SN) is a complex and critical region of the brain wherein Parkinson's disease (PD) arises from the degeneration of dopaminergic neurons. Miniature SN‐like structures (mini‐SNLSs) constructed from novel combination of nanomaterials and cell technologies exhibit promise as potentially curative cell therapies for PD. In this work, a rapid self‐organization of mini‐SNLS, with an organizational structure and neuronal identities similar to those of the SN in vivo, is achieved by differentiating neural stem cells in vitro on biocompatible silica nanozigzags (NZs) sculptured by glancing angle deposition, without traditional chemical growth factors. The differentiated neurons exhibit electrophysiological activity in vitro. Diverse physical cues and signaling pathways that are determined by the nanomatrices and lead to the self‐organization of the mini‐SNLSs are clarified and elucidated. In vivo, transplantation of the neurons from a mini‐SNLS results in an early and progressive amelioration of PD in rats. The sculptured medical device reported here enables the rapid and specific self‐organization of region‐specific and functional brain‐like structures without an undesirable prognosis. This development provides promising and significant insights into the screening of potentially curative drugs and cell therapies for PD.

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Section: Introductionmentioning

confidence: 99%

Extracellular Nanomatrix‐Induced Self‐Organization of Neural Stem Cells into Miniature Substantia Nigra‐Like Structures with Therapeutic Effects on Parkinsonian Rats

et al. 2019

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“…The differentiation of iPSC intocerebral organoids relies onpatterning according to intrinsic signalling, and this therefore can result in substantial heterogeneity between COs (28,31). We wanted to determine whether cerebral organoids would be a suitable system for the analysis of tau isoforms by biochemical assays relying on bulk homogenisation.…”

Section: Cerebral Organoidsshow Highly Heterogeneous Tau Expression Lmentioning

confidence: 99%

Engineered Cerebral Organoids Recapitulate Adult Tau Expression and Disease-relevant Changes in Tau Splicing

Lovejoy

Alatza

Arber

et al. 2020

Preprint

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The tauopathies are a collection of clinically and pathologically diverse neurodegenerative disorders characterised by tau pathology. The tau protein exists as multiple protein isoforms in the adult human CNS, generated by alternative splicing of the MAPT gene. Disruptions to tau splicing are associated with a number of tauopathies, however, in vitro and in vivo models to understand the consequences of disrupted tau splicing have been lacking, due in part to species differences in tau splicing and the developmental regulation of tau in human neurons. We investigated the utility of iPSC-derived cerebral organoids to model key aspects of tau biology. Cerebral organoids showed high variability in neuronal content and tau expression. To reduce this heterogeneity, we generated engineered cerebral organoids (enCORs), which use a floating scaffold to increase the efficiency of neural induction and reduce heterogeneity. We show that enCORs provide a robust and reproducible in vitro system for the analysis of tau expression and splicing in a 3D model. To investigate the effect of tau mutations, we generated enCORs from an isogenic series of iPSC with the MAPT 10+16 and P301S mutations. The presence of tau splicing mutations results in disease-associated alterations in tau expression, specifically a dose-dependent increase in 4R tau isoforms in the presence of the MAPT 10+16 variant. While the developmental regulation of tau splicing is conserved, maturation of tau splicing is accelerated in 3D cultures compared to 2D cultures. Finally, enCORs with coding mutations in MAPT are able to produce seed-competent tau species, suggesting enCORs recapitulate early features of tau pathology. In summary, enCORs provide a novel, robust in vitro system for the study of tau in development and disease.

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“…Contrarily to the “intrinsic” self-patterning protocol, patterning of organoids using inductive signals and optimised bioreactors, as conducted by Qian et al (2016), led to the development of more consistent region specific organoids which were less influenced by batch variability. Optimal patterning and the relevant reproduction of proper developmental axes requires a spatiotemporally defined gradients of morphogens, which is challenging to achieve in culture; it has been suggested that a way to circumvent this could be through the use of slow-releasing microbeads to establish a morphogen gradient (Lee et al, 2011; Sun et al, 2018). In contrast, a recent study revealed that the removal of inductive factors such as those used for the dual SMAD inhibition during the EB differentiation stage, or refraining from using maturating growth factors in culture medium during the organoid stage (such as BDNF, GDNF and TGF-β), yields more optimal organoids with reduced inter and intra batch variability in terms of reproducibility, size, growth and neural cell composition and maturity (Yakoub and Sadek, 2018).…”

Section: Current Caveats and Advancement In The Organoid Technologymentioning

confidence: 99%

Organs to Cells and Cells to Organoids: The Evolution of in vitro Central Nervous System Modelling

Pacitti

Privolizzi

Bax

2019

Front. Cell. Neurosci.

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With 100 billion neurons and 100 trillion synapses, the human brain is not just the most complex organ in the human body, but has also been described as “the most complex thing in the universe.” The limited availability of human living brain tissue for the study of neurogenesis, neural processes and neurological disorders has resulted in more than a century-long strive from researchers worldwide to model the central nervous system (CNS) and dissect both its striking physiology and enigmatic pathophysiology. The invaluable knowledge gained with the use of animal models and post mortem human tissue remains limited to cross-species similarities and structural features, respectively. The advent of human induced pluripotent stem cell (hiPSC) and 3-D organoid technologies has revolutionised the approach to the study of human brain and CNS in vitro , presenting great potential for disease modelling and translational adoption in drug screening and regenerative medicine, also contributing beneficially to clinical research. We have surveyed more than 100 years of research in CNS modelling and provide in this review an historical excursus of its evolution, from early neural tissue explants and organotypic cultures, to 2-D patient-derived cell monolayers, to the latest development of 3-D cerebral organoids. We have generated a comprehensive summary of CNS modelling techniques and approaches, protocol refinements throughout the course of decades and developments in the study of specific neuropathologies. Current limitations and caveats such as clonal variation, developmental stage, validation of pluripotency and chromosomal stability, functional assessment, reproducibility, accuracy and scalability of these models are also discussed.

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Translational potential of human brain organoids

Cited by 36 publications

References 80 publications

Extracellular Nanomatrix‐Induced Self‐Organization of Neural Stem Cells into Miniature Substantia Nigra‐Like Structures with Therapeutic Effects on Parkinsonian Rats

Extracellular Nanomatrix‐Induced Self‐Organization of Neural Stem Cells into Miniature Substantia Nigra‐Like Structures with Therapeutic Effects on Parkinsonian Rats

Engineered Cerebral Organoids Recapitulate Adult Tau Expression and Disease-relevant Changes in Tau Splicing

Organs to Cells and Cells to Organoids: The Evolution of in vitro Central Nervous System Modelling

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