scholarly journals In vitro models for neurotoxicology research

2015 ◽  
Vol 4 (4) ◽  
pp. 801-842 ◽  
Author(s):  
Daniel José Barbosa ◽  
João Paulo Capela ◽  
Maria de Lourdes Bastos ◽  
Félix Carvalho
Keyword(s):  
Nervous System ◽  
Cell Types ◽  
In Vitro Models ◽  
Functional Characteristics ◽  
Multiple Functions ◽  
Complex Organization

The nervous system has a highly complex organization, including many cell types with multiple functions, with an intricate anatomy and unique structural and functional characteristics; the study of its (dys)functionality following exposure to xenobiotics, neurotoxicology, constitutes an important issue in neurosciences.

In Vitro Testing of Neurotoxicity

1990 ◽  
Vol 18 (1_part_1) ◽  
pp. 153-179
Author(s):  
Erik Walum ◽  
Elisabeth Hansson ◽  
Alan L. Harvey
Keyword(s):  
Nervous System ◽  
Ex Vivo ◽  
Cell Types ◽  
Biochemical Properties ◽  
In Vitro Models ◽  
Model Systems ◽  
Culture Methods ◽  
Developmental Potential

Many of the toxic compounds that are at large in the environment represent a risk to our neuronal functions. Chemicals may have a direct or indirect effect on the nervous system and they may interfere with general biochemical properties or specific neuronal structures and processes. In this review, a brief presentation of the major neurotoxicological targets is given, together with a discussion of some aspects of the use of different in vitro models for screening purposes and mechanistic studies. It is believed that in vitro methods offer special opportunities for the development of new neurotoxicological assays, and that this development will mainly involve cultured model systems. Therefore, a presentation of nerve and glia tissue culture methods is given, followed by an overview of how information on the action of mercury and mercurials, excitotoxins and acrylamide has been obtained through the use of cultured cell models. It is concluded that the developmental potential in cell neurotoxicology lies within the areas of separation and identification of cells representative for different structures in the nervous system, co-cultivation of different cell types, in vivo/in vitro (ex vivo) procedures, chemically defined media, metabolic competent cultures of human cells and improved physiological conditions for cultivation and exposure.

scholarly journals Zika Virus Infection Leads to Demyelination and Axonal Injury in Mature CNS Cultures

Viruses ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 91
Author(s):  
Verena Schultz ◽  
Stephanie L. Cumberworth ◽  
Quan Gu ◽  
Natasha Johnson ◽  
Claire L. Donald ◽  
...  
Keyword(s):  
Nervous System ◽  
Neural Development ◽  
Zika Virus ◽  
Developmental Stages ◽  
Cell Types ◽  
Neural Cells ◽  
Zikv Infection ◽  
Axonal Pathology ◽  
Time Frames

Understanding how Zika virus (Flaviviridae; ZIKV) affects neural cells is paramount in comprehending pathologies associated with infection. Whilst the effects of ZIKV in neural development are well documented, impact on the adult nervous system remains obscure. Here, we investigated the effects of ZIKV infection in established mature myelinated central nervous system (CNS) cultures. Infection incurred damage to myelinated fibers, with ZIKV-positive cells appearing when myelin damage was first detected as well as axonal pathology, suggesting the latter was a consequence of oligodendroglia infection. Transcriptome analysis revealed host factors that were upregulated during ZIKV infection. One such factor, CCL5, was validated in vitro as inhibiting myelination. Transferred UV-inactivated media from infected cultures did not damage myelin and axons, suggesting that viral replication is necessary to induce the observed effects. These data show that ZIKV infection affects CNS cells even after myelination—which is critical for saltatory conduction and neuronal function—has taken place. Understanding the targets of this virus across developmental stages including the mature CNS, and the subsequent effects of infection of cell types, is necessary to understand effective time frames for therapeutic intervention.

scholarly journals Effects of Platelet-Rich Plasma on Cellular Populations of the Central Nervous System: The Influence of Donor Age

2021 ◽  
Vol 22 (4) ◽  
pp. 1725
Author(s):  
Diego Delgado ◽  
Ane Miren Bilbao ◽  
Maider Beitia ◽  
Ane Garate ◽  
Pello Sánchez ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cellular Response ◽  
Platelet Rich Plasma ◽  
Biological Response ◽  
In Vitro Models ◽  
Molecular Composition ◽  
Cellular Models ◽  
The Central Nervous System

Platelet-rich plasma (PRP) is a biologic therapy that promotes healing responses across multiple medical fields, including the central nervous system (CNS). The efficacy of this therapy depends on several factors such as the donor’s health status and age. This work aims to prove the effect of PRP on cellular models of the CNS, considering the differences between PRP from young and elderly donors. Two different PRP pools were prepared from donors 65–85 and 20–25 years old. The cellular and molecular composition of both PRPs were analyzed. Subsequently, the cellular response was evaluated in CNS in vitro models, studying proliferation, neurogenesis, synaptogenesis, and inflammation. While no differences in the cellular composition of PRPs were found, the molecular composition of the Young PRP showed lower levels of inflammatory molecules such as CCL-11, as well as the presence of other factors not found in Aged PRP (GDF-11). Although both PRPs had effects in terms of reducing neural progenitor cell apoptosis, stabilizing neuronal synapses, and decreasing inflammation in the microglia, the effect of the Young PRP was more pronounced. In conclusion, the molecular composition of the PRP, conditioned by the age of the donors, affects the magnitude of the biological response.

scholarly journals Modelling the Human Placental Interface In Vitro—A Review

Micromachines ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 884
Author(s):  
Marta Cherubini ◽  
Scott Erickson ◽  
Kristina Haase
Keyword(s):  
Drug Testing ◽  
Cell Types ◽  
In Vitro Models ◽  
Placental Development ◽  
Scientific Challenge ◽  
Induced Pluripotent ◽  
And Function ◽  
And Control

Acting as the primary link between mother and fetus, the placenta is involved in regulating nutrient, oxygen, and waste exchange; thus, healthy placental development is crucial for a successful pregnancy. In line with the increasing demands of the fetus, the placenta evolves throughout pregnancy, making it a particularly difficult organ to study. Research into placental development and dysfunction poses a unique scientific challenge due to ethical constraints and the differences in morphology and function that exist between species. Recently, there have been increased efforts towards generating in vitro models of the human placenta. Advancements in the differentiation of human induced pluripotent stem cells (hiPSCs), microfluidics, and bioprinting have each contributed to the development of new models, which can be designed to closely match physiological in vivo conditions. By including relevant placental cell types and control over the microenvironment, these new in vitro models promise to reveal clues to the pathogenesis of placental dysfunction and facilitate drug testing across the maternal–fetal interface. In this minireview, we aim to highlight current in vitro placental models and their applications in the study of disease and discuss future avenues for these in vitro models.

scholarly journals Production of Human Pluripotent Stem Cell-Derived Hepatic Cell Lineages and Liver Organoids: Current Status and Potential Applications

2020 ◽  
Vol 7 (2) ◽  
pp. 36 ◽  
Author(s):  
João P. Cotovio ◽  
Tiago G. Fernandes
Keyword(s):  
Cell Types ◽  
In Vitro Models ◽  
Hepatic Cell ◽  
Current Status ◽  
Organ Shortage ◽  
Cell Lineages ◽  
Potential Applications ◽  
Liver Organoids

Liver disease is one of the leading causes of death worldwide, leading to the death of approximately 2 million people per year. Current therapies include orthotopic liver transplantation, however, donor organ shortage remains a great challenge. In addition, the development of novel therapeutics has been limited due to the lack of in vitro models that mimic in vivo liver physiology. Accordingly, hepatic cell lineages derived from human pluripotent stem cells (hPSCs) represent a promising cell source for liver cell therapy, disease modelling, and drug discovery. Moreover, the development of new culture systems bringing together the multiple liver-specific hepatic cell types triggered the development of hPSC-derived liver organoids. Therefore, these human liver-based platforms hold great potential for clinical applications. In this review, the production of the different hepatic cell lineages from hPSCs, including hepatocytes, as well as the emerging strategies to generate hPSC-derived liver organoids will be assessed, while current biomedical applications will be highlighted.

Understanding the Physiology of the Blood-Brain Barrier: In Vitro Models

Physiology ◽  
1998 ◽  
Vol 13 (6) ◽  
pp. 287-293 ◽  
Author(s):  
Gerald A. Grant ◽  
N. Joan Abbott ◽  
Damir Janigro
Keyword(s):  
Central Nervous System ◽  
Tissue Culture ◽  
Nervous System ◽  
Blood Brain Barrier ◽  
In Vitro Models ◽  
Brain Barrier ◽  
Blood Brain ◽  
Brain Tissue Culture ◽  
The Brain

Endothelial cells exposed to inductive central nervous system factors differentiate into a blood-brain barrier phenotype. The blood-brain barrier frequently obstructs the passage of chemotherapeutics into the brain. Tissue culture systems have been developed to reproduce key properties of the intact blood-brain barrier and to allow for testing of mechanisms of transendothelial drug permeation.

scholarly journals Mitochondrial Calcium Uptake Capacity Modulates Neocortical Excitability

2013 ◽  
Vol 33 (7) ◽  
pp. 1115-1126 ◽  
Author(s):  
Basavaraju G Sanganahalli ◽  
Peter Herman ◽  
Fahmeed Hyder ◽  
Sridhar S Kannurpatti
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cell Types ◽  
Dependent Manner ◽  
Evoked Responses ◽  
Blood Oxygen Level ◽  
Calcium Uniporter ◽  
Sensory Evoked

Local calcium (Ca2 +) changes regulate central nervous system metabolism and communication integrated by subcellular processes including mitochondrial Ca2 + uptake. Mitochondria take up Ca2 + through the calcium uniporter (mCU) aided by cytoplasmic microdomains of high Ca2 +. Known only in vitro, the in vivo impact of mCU activity may reveal Ca2 + -mediated roles of mitochondria in brain signaling and metabolism. From in vitro studies of mitochondrial Ca2 + sequestration and cycling in various cell types of the central nervous system, we evaluated ranges of spontaneous and activity-induced Ca2 + distributions in multiple subcellular compartments in vivo. We hypothesized that inhibiting (or enhancing) mCU activity would attenuate (or augment) cortical neuronal activity as well as activity-induced hemodynamic responses in an overall cytoplasmic and mitochondrial Ca2 + -dependent manner. Spontaneous and sensory-evoked cortical activities were measured by extracellular electrophysiology complemented with dynamic mapping of blood oxygen level dependence and cerebral blood flow. Calcium uniporter activity was inhibited and enhanced pharmacologically, and its impact on the multimodal measures were analyzed in an integrated manner. Ru360, an mCU inhibitor, reduced all stimulus-evoked responses, whereas Kaempferol, an mCU enhancer, augmented all evoked responses. Collectively, the results confirm aforementioned hypotheses and support the Ca2 + uptake-mediated integrative role of in vivo mitochondria on neocortical activity.

TMOD-21. A NOVEL IN-VITRO METHOD TO MODEL MACROPHAGES IN GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi220-vi220
Author(s):  
Hasan Alrefai ◽  
Andee Beierle ◽  
Lauren Nassour ◽  
Nicholas Eustace ◽  
Zeel Patel ◽  
...  
Keyword(s):  
Cell Types ◽  
In Vitro Models ◽  
Tumor Initiating Cells ◽  
Serum Free ◽  
Brain Tumor Initiating Cells ◽  
Multiple Cell ◽  
Anti Inflammatory ◽  
Free Media ◽  
Inflammatory Macrophages

Abstract BACKGROUND The GBM tumor microenvironment (TME) is comprised of a plethora of cancerous and non-cancerous cells that contribute to GBM growth, invasion, and chemoresistance. In-vitro models of GBM typically fail to incorporate multiple cell types. Others have addressed this problem by employing 3D bioprinting to incorporate astrocytes and macrophages in an extracellular matrix; however, they used serum-containing media and classically polarized anti-inflammatory macrophages. Serum has been shown to cause GBM brain-tumor initiating cells to lose their stem-like properties, highlighting the importance of excluding it from these models. Additionally, tumor-associated macrophages (TAMs) do not adhere to the traditional M2 phenotype. METHODS THP-1 monocytes and normal human astrocytes (NHAs) were transitioned into serum-free HL-1 and neurobasal-based media, respectively. Monocytes were stimulated towards a macrophage-like state with PMA and polarized by co-culturing them with GBM patient-derived xenograft(PDX) lines, using a transwell insert. CD206 expression was used to validate polarization and a cytokine array was used to characterize the cells. RESULTS There was no difference in proliferation rates at 72 hours for THP-1 monocytes grown in serum-free HL-1 media compared to serum-containing RPMI 1640 (p > 0.95). Macrophages polarized via transwell inserts expressed the lymphocyte chemoattractant protein, CCL2, whereas resting(M0), pro-inflammatory(M1), and anti-inflammatory(M2) macrophages did not. Additionally, these macrophages expressed more CXCL1 and IL-1ß relative to M1 macrophages. We have also demonstrated a method to maintain a tri-culture model of GBM PDX cells, NHAs, and TAMs in a serum-free media that supports the growth/maintenance of all cell types. CONCLUSIONS We have demonstrated a novel method by which we can polarize macrophages towards a tumor-supportive phenotype that differs in cytokine expression from traditionally polarized macrophages. This higher-fidelity method of modeling TAMs in GBM can aid in the development of targeted therapeutics that may one day enter the clinic in hopes of improving outcomes in GBM.

scholarly journals Microphysiological Systems: A Pathologist’s Perspective

2020 ◽  
Vol 57 (3) ◽  
pp. 358-368
Author(s):  
Radhakrishna Sura ◽  
Terry Van Vleet ◽  
Brian R. Berridge
Keyword(s):  
Drug Discovery ◽  
Biomedical Research ◽  
Interdisciplinary Collaboration ◽  
Cell Types ◽  
In Vitro Models ◽  
In Vitro Methods ◽  
Microphysiological Systems ◽  
Regulatory Acceptance

High-throughput in vitro models lack human-relevant complexity, which undermines their ability to accurately mimic in vivo biologic and pathologic responses. The emergence of microphysiological systems (MPS) presents an opportunity to revolutionize in vitro modeling for both basic biomedical research and applied drug discovery. The MPS platform has been an area of interdisciplinary collaboration to develop new, predictive, and reliable in vitro methods for regulatory acceptance. The current MPS models have been developed to recapitulate an organ or tissue on a smaller scale. However, the complexity of these models (ie, including all cell types present in the in vivo tissue) with appropriate structural, functional, and biochemical attributes are often not fully characterized. Here, we provide an overview of the capabilities and limitations of the microfluidic MPS model (aka organs-on-chips) within the scope of drug development. We recommend the engagement of pathologists early in the MPS design, characterization, and validation phases, because this will enable development of more robust and comprehensive MPS models that can accurately replicate normal biology and pathophysiology and hence be more predictive of human responses.

Computational profiling of hiPSC-derived heart organoids reveals chamber defects associated with Ebstein’s anomaly

2020 ◽  
Author(s):  
Wei Feng ◽  
Hannah Schriever ◽  
Shan Jiang ◽  
Abha Bais ◽  
Dennis Kostka ◽  
...  
Keyword(s):  
Heart Development ◽  
Cell Types ◽  
In Vitro Models ◽  
Ebstein’S Anomaly ◽  
Great Promise ◽  
Heart Cells ◽  
Ebstein's Anomaly ◽  
Disease States ◽  
Human Fetal Heart

AbstractHeart organoids have the potential to generate primary heart-like anatomical structures and hold great promise as in vitro models for cardiac disease. However, their properties have not yet been carefully studied, which hinders a wider spread application. Here we report the development of differentiation systems for ventricular and atrial heart organoids, enabling the study of heart disease with chamber defects. We show that our systems generate organoids comprising of major cardiac cell types, and we used single cell RNA sequencing together with sample multiplexing to characterize the cells we generate. To that end, we also developed a machine learning label transfer approach lever-aging cell type, chamber, and laterality annotations available for primary human fetal heart cells. We then used this model to analyze organoid cells from an isogeneic line carrying an Ebstein’s anomaly associated genetic variant, and we successfully recapitulated the disease’s atrialized ventricular defects. In summary, we have established a workflow integrating heart organoids and computational analysis to model heart development in normal and disease states.

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