Unprecedented Potential for Neural Drug Discovery Based on Self-Organizing hiPSC Platforms

Cota-Coronado, Agustín; Durnall, Jennifer C.; Díaz, Néstor Fabián; Thompson, Lachlan H.; Díaz-Martínez, N.E.

doi:10.3390/molecules25051150

Cited by 9 publications

(7 citation statements)

References 65 publications

(70 reference statements)

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“…hiPSCs are especially relevant to neural tissue engineering since brain cells from patients are rarely available for research. hiPSC-derived neural tissues could become a powerful diagnostic and prognostic tool for drug screening [60][61][62]. Additionally, bioinks can efficiently mimic the extracellular matrix found in brain tissue.…”

Section: Introductionmentioning

confidence: 99%

Physical and Mechanical Characterization of Fibrin-Based Bioprinted Constructs Containing Drug-Releasing Microspheres for Neural Tissue Engineering Applications

et al. 2021

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Three-dimensional bioprinting can fabricate precisely controlled 3D tissue constructs. This process uses bioinks—specially tailored materials that support the survival of incorporated cells—to produce tissue constructs. The properties of bioinks, such as stiffness and porosity, should mimic those found in desired tissues to support specialized cell types. Previous studies by our group validated soft substrates for neuronal cultures using neural cells derived from human-induced pluripotent stem cells (hiPSCs). It is important to confirm that these bioprinted tissues possess mechanical properties similar to native neural tissues. Here, we assessed the physical and mechanical properties of bioprinted constructs generated from our novel microsphere containing bioink. We measured the elastic moduli of bioprinted constructs with and without microspheres using a modified Hertz model. The storage and loss modulus, viscosity, and shear rates were also measured. Physical properties such as microstructure, porosity, swelling, and biodegradability were also analyzed. Our results showed that the elastic modulus of constructs with microspheres was 1032 ± 59.7 Pascal (Pa), and without microspheres was 728 ± 47.6 Pa. Mechanical strength and printability were significantly enhanced with the addition of microspheres. Thus, incorporating microspheres provides mechanical reinforcement, which indicates their suitability for future applications in neural tissue engineering.

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Section: Introductionmentioning

confidence: 99%

Physical and Mechanical Characterization of Fibrin-Based Bioprinted Constructs Containing Drug-Releasing Microspheres for Neural Tissue Engineering Applications

et al. 2021

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“…Region-specific neural organoids can be created by the differentiation of hiPSC [ 40 ]. These organoids can recapitulate distinct brain regions that arise during human brain development, as it has been shown in cortical plate [ 41 ], forebrain [ 42 ], midbrain [ 43 ], and hypothalamic organoids [ 44 ].…”

Section: Brain Organoids To Investigate Brain Disordersmentioning

confidence: 99%

Brain and Retinal Organoids for Disease Modeling: The Importance of In Vitro Blood–Brain and Retinal Barriers Studies

Martinelli

Tayebati

Tomassoni

et al. 2022

Cells

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Brain and retinal organoids are functional and dynamic in vitro three-dimensional (3D) structures derived from pluripotent stem cells that spontaneously organize themselves to their in vivo counterparts. Here, we review the main literature data of how these organoids have been developed through different protocols and how they have been technically analyzed. Moreover, this paper reviews recent advances in using organoids to model neurological and retinal diseases, considering their potential for translational applications but also pointing out their limitations. Since the blood–brain barrier (BBB) and blood–retinal barrier (BRB) are understood to play a fundamental role respectively in brain and eye functions, both in health and in disease, we provide an overview of the progress in the development techniques of in vitro models as reliable and predictive screening tools for BBB and BRB-penetrating compounds. Furthermore, we propose potential future directions for brain and retinal organoids, in which dedicated biobanks will represent a novel tool for neuroscience and ophthalmology research.

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“…For example, similar systems have already been employed clinically in the estimation of survival prognosis in patients diagnosed with eye melanoma (Damato et al, 2008), thyroid cancer (Mourad et al, 2020), glioblastoma multiforme (Hao et al, 2018), among other diseases (Kourou et al, 2015;Zhu et al, 2020). Indeed, AI-based technologies can be wisely applied to compile, digest and interpret "hidden knowledge" in large datasets and make the data usable to researchers in the ALS field and beyond (Ko et al, 2014;Kusumoto and Yuasa, 2019;Cota-Coronado et al, 2020;Zhou and Manser, 2020).…”

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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Unprecedented Potential for Neural Drug Discovery Based on Self-Organizing hiPSC Platforms

Cited by 9 publications

References 65 publications

Physical and Mechanical Characterization of Fibrin-Based Bioprinted Constructs Containing Drug-Releasing Microspheres for Neural Tissue Engineering Applications

Physical and Mechanical Characterization of Fibrin-Based Bioprinted Constructs Containing Drug-Releasing Microspheres for Neural Tissue Engineering Applications

Brain and Retinal Organoids for Disease Modeling: The Importance of In Vitro Blood–Brain and Retinal Barriers Studies

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

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