Modeling neurodegenerative diseases with cerebral organoids and other three-dimensional culture systems: focus on Alzheimer’s disease

Venkataraman, Lalitha; Fair, Summer R; McElroy, Craig A.; Hester, Mark E.; Fu, Hongjun

doi:10.1007/s12015-020-10068-9

Cited by 32 publications

(19 citation statements)

References 217 publications

(417 reference statements)

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“…Further understanding of this uniquely human immune mechanism, and its impact on AD, in terms of whether it is protective or destructive would open new areas of treatment strategies with the potential for resolving the translational gap. This iPSC resource is adaptable for high throughput 3D modeling of human tissue by creating cerebral organoids and 3D bioprinting [ 24 , 25 ]. The combination of the human environment using hiPSCs and the emergence of 3D modeling technology may facilitate qualitative progress in drug discovery in general [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, in the context of a uniquely human gene, functional readout in the human cellular and tissue environment is paramount. Drug development in human 3D tissue equivalents is likely more to be prone to artefacts compared to in vivo animal models; however, with appropriate controls and orthogonal experimental methods, this can be overcome [ 24 ]. While the experimental phase is more involved, emerging drug candidates from 3D human screens will likely result in a more direct human translation.…”

Section: Discussionmentioning

confidence: 99%

“…We tested the hypothesis in microglia-like (MGL) cells that were differentiated from the human parent and isogenic induced pluripotent stem cells (iPSCs) to provide the human context [ 20 , 21 ]. To recapitulate the complexity of the human brain, these genome-edited iPSC lines can serve as a genotype-specific 3D model of human tissue, including cerebral organoids and 3D bioprinting [ 24 , 25 ]. Alzheimer’s disease has been challenging to model in animals in general and has resulted in disappointing translational outcomes regarding drug discovery [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

“…Alzheimer’s disease has been challenging to model in animals in general and has resulted in disappointing translational outcomes regarding drug discovery [ 26 ]. The complexity, the temporal and spatial resolution, and cell-type diversity of the human brain are oversimplified in 2D cell culture systems [ 24 ]. The combination of the human environment using hiPSCs (human iPSCs) and the emergence of 3D modeling technology may facilitate exponential progress in drug discovery with direct human translation [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

iPSC-Derived Microglia for Modeling Human-Specific DAMP and PAMP Responses in the Context of Alzheimer’s Disease

Ihnatovych

Birkaya

Notari

et al. 2020

IJMS

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Neuroinflammation in Alzheimer’s disease (AD) has been the focus for identifying targetable pathways for drug development. The role of amyloid beta (Aβ), a prototype of damage-associated molecular patterns (DAMPs), has been implicated in triggering an inflammatory response. As alpha7 nicotinic acetylcholine receptor (α7 nAChR) binds Aβ with high affinity, α7 nAChR may play a role in Aβ-induced neuroinflammation. The conundrum of how α7 nAChR as the mediator of the cholinergic anti-inflammatory response may trigger an inflammatory response has not been resolved. CHRFAM7A, the uniquely human fusion gene between ULK4 and CHRNA7, is a negative regulator of α7 nAChR ionotropic function. To provide the human context, isogenic induced pluripotent stem cell (iPSC) lines were developed from CHRFAM7A null and carrier individuals by genome-editing the null line using TALENs to knock-in CHRFAM7A. In iPSC-derived microglia-like cells, CHRFAM7A mitigated Aβ uptake through the α7 nAChR. Despite the lower Aβ uptake, the presence of CHRFAM7A was associated with an innate immune response that was characterized by NF-κB activation and NF-κB target transcription (TNFA, IL6, and IL1B). LPS, a prototype PAMP, induced a heightened immune response in CHRFAM7A carriers. CHRFAM7A modified the dynamics of NF-κB translocation by prolonging its nuclear presence. CHRFAM7A modified the α7 nAChR metabotropic function, resulting in a human-specific innate immune response. This iPSC model provided an opportunity to elucidate the mechanism and establish high throughput screens.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

iPSC-Derived Microglia for Modeling Human-Specific DAMP and PAMP Responses in the Context of Alzheimer’s Disease

Ihnatovych

Birkaya

Notari

et al. 2020

IJMS

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“…The causes of AD are pleiotropic, but 95% of all cases are sporadic 7 . Current AD three-dimensional (3D) organoid models (mostly based on APP and presenilin mutations) do not show progressive tau aggregation beyond phosphorylated tau or develop neurodegeneration 1,8,9 . The di culty in producing a human organoid model that exhibits tau pathology and neurodegeneration, combined with the inadequacies of current animal models for AD has stymied the eld in its quest to understand the nature of sporadic AD and develop therapies able to delay AD disease progression.…”

Section: Main Textmentioning

confidence: 99%

Single cell transcriptomic profiling of neurodegeneration mediated by tau propagation in a novel 3D neuron-astrocyte coculture model

Wolozin¹,

Rickner²,

Jiang³

et al. 2021

Preprint

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Research into neurodegeneration has been hampered by lack of systems that accurately recapitulate neurodegenerative processes1. Propagation of tau through a ‘prion-like’ process has emerged as an important aspect of neurodegenerative diseases including Alzheimer’s disease2. However, molecular mechanism of tau propagation is still largely unknown and a human 3D cellular model is still lacking. Here, we report development of the AstAD system, which uses human iPSCs to create neuron-astrocyte spheroids that incorporates propagation of toxic tau oligomers3,4. Single cell transcriptomic profiling reveals roles for ribosomes, TNF mediated neuroinflammation and heat shock proteins (HSP) as major elements of the disease stress response. Treatment with the HSP90 inhibitor PU-H71, which is selective for the dysfunctional HSP epichaperome, demonstrates reduction of pathology and neurodegeneration in the AstAD system5.

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Engineered extracellular matrices facilitate brain organoids from human pluripotent stem cells

Muñiz,

Topal,

Brooks

et al. 2023

Ann Clin Transl Neurol

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Objective Brain organoids are miniaturized in vitro brain models generated from pluripotent stem cells, which resemble full‐sized brain more closely than conventional two‐dimensional cell cultures. Although brain organoids mimic the human brain's cell‐to‐cell network interactions, they generally fail to faithfully recapitulate cell‐to‐matrix interactions. Here, an engineered framework, called an engineered extracellular matrix (EECM), was developed to provide support and cell‐to‐matrix interactions to developing brain organoids. Methods We generated brain organoids using EECMs comprised of human fibrillar fibronectin supported by a highly porous polymer scaffold. The resultant brain organoids were characterized by immunofluorescence microscopy, transcriptomics, and proteomics of the cerebrospinal fluid (CSF) compartment. Results The interstitial matrix‐mimicking EECM enhanced neurogenesis, glial maturation, and neuronal diversity from human embryonic stem cells versus conventional protein matrix (Matrigel). Additionally, EECMs supported long‐term culture, which promoted large‐volume organoids containing over 250 μL of CSF. Proteomics analysis of the CSF found it superseded previous brain organoids in protein diversity, as indicated by 280 proteins spanning 500 gene ontology pathways shared with adult CSF. Interpretation Engineered EECM matrices represent a major advancement in neural engineering as they have the potential to significantly enhance the structural, cellular, and functional diversity that can be achieved in advanced brain models.

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Modeling neurodegenerative diseases with cerebral organoids and other three-dimensional culture systems: focus on Alzheimer’s disease

Cited by 32 publications

References 217 publications

iPSC-Derived Microglia for Modeling Human-Specific DAMP and PAMP Responses in the Context of Alzheimer’s Disease

iPSC-Derived Microglia for Modeling Human-Specific DAMP and PAMP Responses in the Context of Alzheimer’s Disease

Single cell transcriptomic profiling of neurodegeneration mediated by tau propagation in a novel 3D neuron-astrocyte coculture model

Engineered extracellular matrices facilitate brain organoids from human pluripotent stem cells

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