Modeling Neurological Disorders with Human Pluripotent Stem Cell-Derived Astrocytes

Suga, Mika; Kondo, Takayuki; Inoue, Haruhisa

doi:10.3390/ijms20163862

Cited by 22 publications

(19 citation statements)

References 82 publications

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“…However, GFAP is not expressed in all mature human astrocytes [ 121 , 122 ]; therefore, a panel of additional astrocyte markers including S100-beta and NDRG2 [ 120 , 123 ] is recommended to confirm astrocyte identity prior to use. Sources of human astrocytes include commercial immortalized (astrocytoma) cell lines [ 124 , 125 , 126 ] and primary cells [ 127 , 128 , 129 ], as well as a growing collection of published protocols to generate iPSC-derived astrocytes, [ 130 , 131 , 132 , 133 ] as reviewed in [ 134 , 135 , 136 ]. Several new differentiation protocols have been published within the last year, including Gatto et al who showed that direct differentiation of astrocytes from fibroblasts retained the age-related transcriptional differences of their donors [ 137 ].…”

Section: Decision Workflow: Factors To Consider When Selecting a Model Systemmentioning

confidence: 99%

Review of Design Considerations for Brain-on-a-Chip Models

et al. 2021

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In recent years, the need for sophisticated human in vitro models for integrative biology has motivated the development of organ-on-a-chip platforms. Organ-on-a-chip devices are engineered to mimic the mechanical, biochemical and physiological properties of human organs; however, there are many important considerations when selecting or designing an appropriate device for investigating a specific scientific question. Building microfluidic Brain-on-a-Chip (BoC) models from the ground-up will allow for research questions to be answered more thoroughly in the brain research field, but the design of these devices requires several choices to be made throughout the design development phase. These considerations include the cell types, extracellular matrix (ECM) material(s), and perfusion/flow considerations. Choices made early in the design cycle will dictate the limitations of the device and influence the end-point results such as the permeability of the endothelial cell monolayer, and the expression of cell type-specific markers. To better understand why the engineering aspects of a microfluidic BoC need to be influenced by the desired biological environment, recent progress in microfluidic BoC technology is compared. This review focuses on perfusable blood–brain barrier (BBB) and neurovascular unit (NVU) models with discussions about the chip architecture, the ECM used, and how they relate to the in vivo human brain. With increased knowledge on how to make informed choices when selecting or designing BoC models, the scientific community will benefit from shorter development phases and platforms curated for their application.

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Section: Decision Workflow: Factors To Consider When Selecting a Model Systemmentioning

confidence: 99%

Review of Design Considerations for Brain-on-a-Chip Models

et al. 2021

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“…The comprehensive work carried out in the field of pluripotent stem cells over the past decade has led to the development of numerous protocols for generating hiPSCs, producing neurons, glia and many other cell types from them, as well as enhanced conditions for in vitro culture (Figure 4) (Roybon et al, 2013;Sances et al, 2016;Tao and Zhang, 2016;Gonzalez et al, 2017;Costamagna et al, 2019;Logan et al, 2019;Savchenko et al, 2019;Suga et al, 2019;Karagiannis and Inoue, 2020;Li and Shi, 2020). Even though we still lack a comprehensive knowledge on the survival requirements of human MNs in vitro, patient-specific MNs can still be used to gain insights into the underlying mechanisms of ALS and to perform screenings to identify drug candidates (Figure 3).…”

Section: Challenges and Future Perspectivesmentioning

confidence: 99%

Harnessing the Potential of Human Pluripotent Stem Cell-Derived Motor Neurons for Drug Discovery in Amyotrophic Lateral Sclerosis: From the Clinic to the Laboratory and Back to the Patient

Lamas

Roybon

2021

Front. Drug. Discov.

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Amyotrophic Lateral Sclerosis (ALS) is a motor neurodegenerative disorder whose cellular hallmarks are the progressive death of motor neurons (MNs) located in the anterior horn of the spinal cord, brainstem and motor cortex, and the formation of intracellular protein aggregates. Over the course of the disease, progressive paralysis takes place, leading to patient death within 3–5 years after the diagnosis. Despite decades of intensive research, only a few therapeutic options exist, with a limited benefit on the disease progression. Preclinical animal models have been very useful to decipher some aspects of the mechanisms underlying ALS. However, discoveries made using transgenic animal models have failed to translate into clinically meaningful therapeutic strategies. Thus, there is an urgent need to find solutions to discover drugs that could impact on the course of the disease, with the ultimate goal to extend the life of patients and improve their quality of life. Induced pluripotent stem cells (iPSCs), similarly to embryonic stem cells (ESCs), have the capacity to differentiate into all three embryonic germ layers, which offers the unprecedented opportunity to access patient-specific central nervous system cells in an inexhaustible manner. Human MNs generated from ALS patient iPSCs are an exciting tool for disease modelling and drug discovery projects, since they display ALS-specific phenotypes. Here, we attempted to review almost 2 decades of research in the field, first highlighting the steps required to efficiently generate MNs from human ESCs and iPSCs. Then, we address relevant ALS studies which employed human ESCs and iPSC-derived MNs that led to the identification of compounds currently being tested in clinical trials for ALS. Finally, we discuss the potential and caveats of using patient iPSC-derived MNs as a platform for drug screening, and anticipate ongoing and future challenges in ALS drug discovery.

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“…More advanced protocols were able to overcome this drawback and reduce differentiation time to as little as 30 days by using NPCs as a starting point [ 112 , 113 ]. Detailed descriptions of differences and commonalities between published astrocyte differentiation protocols are described elsewhere [ 113 , 114 ]. Before the start of glial differentiation, iPSC must pass a neuronal progenitor phase.…”

Section: Astrocytes In Health and Diseasementioning

confidence: 99%

Human iPSC-Derived Glia as a Tool for Neuropsychiatric Research and Drug Development

Heider

Vogel

Volkmer

et al. 2021

IJMS

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Neuropsychiatric disorders such as schizophrenia or autism spectrum disorder represent a leading and growing burden on worldwide mental health. Fundamental lack in understanding the underlying pathobiology compromises efficient drug development despite the immense medical need. So far, antipsychotic drugs reduce symptom severity and enhance quality of life, but there is no cure available. On the molecular level, schizophrenia and autism spectrum disorders correlate with compromised neuronal phenotypes. There is increasing evidence that aberrant neuroinflammatory responses of glial cells account for synaptic pathologies through deregulated communication and reciprocal modulation. Consequently, microglia and astrocytes emerge as central targets for anti-inflammatory treatment to preserve organization and homeostasis of the central nervous system. Studying the impact of neuroinflammation in the context of neuropsychiatric disorders is, however, limited by the lack of relevant human cellular test systems that are able to represent the dynamic cellular processes and molecular changes observed in human tissue. Today, patient-derived induced pluripotent stem cells offer the opportunity to study neuroinflammatory mechanisms in vitro that comprise the genetic background of affected patients. In this review, we summarize the major findings of iPSC-based microglia and astrocyte research in the context of neuropsychiatric diseases and highlight the benefit of 2D and 3D co-culture models for the generation of efficient in vitro models for target screening and drug development.

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Modeling Neurological Disorders with Human Pluripotent Stem Cell-Derived Astrocytes

Cited by 22 publications

References 82 publications

Review of Design Considerations for Brain-on-a-Chip Models

Review of Design Considerations for Brain-on-a-Chip Models

Harnessing the Potential of Human Pluripotent Stem Cell-Derived Motor Neurons for Drug Discovery in Amyotrophic Lateral Sclerosis: From the Clinic to the Laboratory and Back to the Patient

Human iPSC-Derived Glia as a Tool for Neuropsychiatric Research and Drug Development

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