Bioengineered models of Parkinson’s disease using patient-derived dopaminergic neurons exhibit distinct biological profiles in a 3D microenvironment

Fiore, Nicholas J.; Ganat, Yosif; Devkota, Kapil; Batorsky, Rebecca; Lei, Ming; Lee, Kyongbum; Cowen, Lenore; Croft, Gist F.; Noggle, Scott; Nieland, Thomas J.F.; Kaplan, David L.

doi:10.1007/s00018-021-04047-7

Cited by 14 publications

(12 citation statements)

References 144 publications

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“…These approaches require longer acclimation periods for the regeneration of axonal networks, at best, and may lead to suboptimal phenotypic baselines, at worst. Further, our dual stimulation approach combining PD neurotoxins and pro-inflammatory mediators demonstrated to be instrumental for the generation of complex PD-related microenvironments and goes beyond the one-dimensional stimulation approaches employed previously using either mitochondrial stressors [105][106][107] or single genetic mutations of PD risk genes [23,108,[111][112][113]. To the best of our knowledge, this is also the first time that neuroimmune co-cultures are used to promote PDrelated pathologies in vitro.…”

Section: Discussionmentioning

confidence: 95%

“…Thus, the reduced maturation time and high reproducibility of our model could facilitate its use in higher throughput applications such as pharmacological or genetic screening. In addition, the in situ differentiation of DA neurons within our 3D matrices represents a less invasive approach on neuronal network formation than previous 3D bioprinted PD models, which rely on embedding already differentiated DA neurons [105,111]. These approaches require longer acclimation periods for the regeneration of axonal networks, at best, and may lead to suboptimal phenotypic baselines, at worst.…”

Section: Discussionmentioning

confidence: 99%

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Three-dimensional neuroimmune co-culture system for modeling Parkinson’s disease microenvironments in vitro

et al. 2023

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Parkinson’s disease (PD) is a complex and multifaceted neurodegenerative disorder that results from multiple environmental factors and multicellular interactions. Although several PD neuropathologies have been identified and described, the thorough understanding of PD pathophysiology and research has been largely limited by the absence of reliable in vitro models that truly recapitulate PD microenvironments. Here, we propose a neuroimmune co-culture system that models PD neuropathologies by combining relevant multicellular interactions with environments that mimic the brain. This system is composed of: (i) 3D bioprinted cultures of mature human dopaminergic neurons grown on extracellular matrix (ECM)-derived scaffolds doped with electroconductive nanostructures, and (ii) a direct co-culture of human astrocytes and differentiated monocytes that models neuroinflammatory responses. When co-cultured in a transwell format, these two compartments recreate relevant multicellular environments that model Parkinson's disease pathologies after exposure to the neurotoxin A53T α-synuclein. With immunofluorescent staining and gene expression analyses, we show that functional and mature dopaminergic 3D networks are generated within our ECM-derived scaffolds with superior performance to standard 2D cultures. Moreover, by analyzing cytokine secretion, cell surface markers, and gene expression, we define a human monocyte differentiation scheme that allows the appearance of both monocyte-derived macrophages and dendritic cell phenotypes, as well as their optimal co-culture ratios with human astrocytes to recreate synergistic neuroinflammatory responses. We show that the combined response of both compartments to A53T α−synuclein stimulates the formation of intracellular α-synuclein aggregates, induces progressive mitochondrial dysfunction and ROS production, downregulates the expression of synaptic, dopaminergic, and mitophagy-related genes, and promotes the initiation of apoptotic processes within the dopaminergic networks. Most importantly, these intracellular pathologies were comparable or superior to those generated with a rotenone-stimulated 2D control that represents the current standard for in vitro PD models and showed increased resilience towards these neurotoxic insults, allowing the study of disease progression over longer time periods than current models.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Three-dimensional neuroimmune co-culture system for modeling Parkinson’s disease microenvironments in vitro

et al. 2023

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“…Approximately 1μg of total RNA for each sample underwent RNA quality control analyses before library preparation and bulk mRNA sequencing as previously described (54). RNA integrity numbers (RIN) were determined with a Bioanalyzer 2100 (Agilent Technologies, Santa Clara, CA, USA) which indicated minimal RNA degradation.…”

Section: Methodsmentioning

confidence: 99%

“…RNA integrity numbers (RIN) were determined with a Bioanalyzer 2100 (Agilent Technologies, Santa Clara, CA, USA) which indicated minimal RNA degradation. Illumina Novaseq sequencers generated paired-end reads (150bp) at a read depth of 20 million reads (54).…”

Section: Messenger Rna (Mrna) Sequencing and Bioinformatic Analysismentioning

confidence: 99%

Mitochondria dysregulation contributes to secondary neurodegeneration progression post-contusion injury in human 3D in vitro triculture brain tissue model

Liaudanskaya

Fiore

Zhang

et al. 2022

Preprint

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Traumatic Brain injury-induced disturbances in mitochondrial fission-and-fusion dynamics have been linked to the onset and propagation of neuroinflammation and neurodegeneration. However, cell-type-specific contributions and crosstalk between neurons, microglia, and astrocytes in mitochondria-driven neurodegeneration after brain injury remain undefined. We developed a human three-dimensional in vitro triculture tissue model of a contusion injury, composed of neurons, microglia, and astrocytes, and examined the contributions of mitochondrial dysregulation to neuroinflammation and progression of injury-induced neurodegeneration. Pharmacological studies presented here suggest that fragmented mitochondria released by microglia are a key contributor to secondary neuronal damage progression after contusion injury, a pathway that requires astrocyte-microglia crosstalk. Controlling mitochondrial dysfunction thus offers an exciting option for the development of therapies for TBI patients.

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“…Notably, 3D-culture not only needs the consideration of mechanobiology and mechanical parameters, but also relies heavily on biomaterials for technical support. [416,417] Currently, 3D brain models based on human induced pluripotent stem cell (hiPSC) neurons are widely used to recapitulate the major phenotypes and metabolic profiles reminiscent of several neurodegenerative diseases, such as Parkinson's disease [418] and Alzheimer's disease. [419] Within this model, appropriate cell types, mechanical cues, and biomimetic ECM are assembled to mimic physiological and pathological microenvironment of brain.…”

Section: D-culture: Microenvironment Simulation and Organoid Fabricationmentioning

confidence: 99%

A Hierarchical Mechanotransduction System: From Macro to Micro

Cao,

Tian,

Tian

et al. 2023

Advanced Science

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Mechanotransduction is a strictly regulated process whereby mechanical stimuli, including mechanical forces and properties, are sensed and translated into biochemical signals. Increasing data demonstrate that mechanotransduction is crucial for regulating macroscopic and microscopic dynamics and functionalities. However, the actions and mechanisms of mechanotransduction across multiple hierarchies, from molecules, subcellular structures, cells, tissues/organs, to the whole‐body level, have not been yet comprehensively documented. Herein, the biological roles and operational mechanisms of mechanotransduction from macro to micro are revisited, with a focus on the orchestrations across diverse hierarchies. The implications, applications, and challenges of mechanotransduction in human diseases are also summarized and discussed. Together, this knowledge from a hierarchical perspective has the potential to refresh insights into mechanotransduction regulation and disease pathogenesis and therapy, and ultimately revolutionize the prevention, diagnosis, and treatment of human diseases.

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Bioengineered models of Parkinson’s disease using patient-derived dopaminergic neurons exhibit distinct biological profiles in a 3D microenvironment

Cited by 14 publications

References 144 publications

Three-dimensional neuroimmune co-culture system for modeling Parkinson’s disease microenvironments in vitro

Three-dimensional neuroimmune co-culture system for modeling Parkinson’s disease microenvironments in vitro

Mitochondria dysregulation contributes to secondary neurodegeneration progression post-contusion injury in human 3D in vitro triculture brain tissue model

A Hierarchical Mechanotransduction System: From Macro to Micro

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