Folding brains: from development to disease modeling

2021 ◽  
Author(s):  
Lucia Del Valle Anton ◽  
Victor Borrell
Keyword(s):  
Cerebral Cortex ◽  
Disease Modeling ◽  
Current Knowledge ◽  
In Vitro Models ◽  
Human Cortex ◽  
Large Size ◽  
Stem And Progenitor Cells ◽  
Key Events ◽  
Fine Tune

The human brain is characterized by the large size and intricate folding of its cerebral cortex, which are fundamental for our higher cognitive function and frequently altered in pathological dysfunction. Cortex folding is not unique to humans, nor even to primates, but is common across mammals. Cortical growth and folding are the result of complex developmental processes that involve neural stem and progenitor cells and their cellular lineages, the migration and differentiation of neurons, and the genetic programs that regulate and fine-tune these processes. All these factors combined generate mechanical stress and strain on the developing neural tissue, which ultimately drives orderly cortical deformation and folding. In this review we examine and summarize the current knowledge on the molecular, cellular, histogenic and mechanical mechanisms that are involved in and influence folding of the cerebral cortex, and how they emerged and changed during mammalian evolution. We discuss the main types of pathological malformations of human cortex folding, their specific developmental origin, and how investigating their genetic causes has illuminated our understanding of key events involved. We close our review by presenting the state-of-the-art animal and in vitro models of cortex folding that are currently used to study these devastating developmental brain disorders in children, and what are the main challenges that remain ahead of us to fully understand brain folding.

Modulation of Matrix Metalloproteinases by Plant-Derived Products

2020 ◽  
Vol 20 ◽  
Author(s):  
Nur Najmi Mohamad Anuar ◽  
Nurul Iman Natasya Zulkafali ◽  
Azizah Ugusman
Keyword(s):  
Clinical Trials ◽  
Natural Products ◽  
Matrix Metalloproteinases ◽  
Animal Studies ◽  
Current Knowledge ◽  
In Vitro Models ◽  
In Vivo Studies ◽  
Extracellular Matrix Components

: Matrix metalloproteinases (MMPs) are a group of zinc-dependent metallo-endopeptidase that are responsible towards the degradation, repair and remodelling of extracellular matrix components. MMPs play an important role in maintaining a normal physiological function and preventing diseases such as cancer and cardiovascular diseases. Natural products derived from plants have been used as traditional medicine for centuries. Its active compounds, such as catechin, resveratrol and quercetin, are suggested to play an important role as MMPs inhibitors, thereby opening new insights into their applications in many fields, such as pharmaceutical, cosmetic and food industries. This review summarises the current knowledge on plant-derived natural products with MMP-modulating activities. Most of the reviewed plant-derived products exhibit an inhibitory activity on MMPs. Amongst MMPs, MMP-2 and MMP-9 are the most studied. The expression of MMPs is inhibited through respective signalling pathways, such as MAPK, NF-κB and PI3 kinase pathways, which contribute to the reduction in cancer cell behaviours, such as proliferation and migration. Most studies have employed in vitro models, but a limited number of animal studies and clinical trials have been conducted. Even though plant-derived products show promising results in modulating MMPs, more in vivo studies and clinical trials are needed to support their therapeutic applications in the future.

scholarly journals From NAFLD to MAFLD: Aligning Translational In Vitro Research to Clinical Insights

Biomedicines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 161
Author(s):  
Alexandra Gatzios ◽  
Matthias Rombaut ◽  
Karolien Buyl ◽  
Joery De Kock ◽  
Robim M. Rodrigues ◽  
...  
Keyword(s):  
Liver Disease ◽  
Drug Development ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Drug Testing ◽  
Disease Modeling ◽  
In Vitro Models ◽  
Alcoholic Fatty Liver ◽  
Short Term Exposure

Although most same-stage non-alcoholic fatty liver disease (NAFLD) patients exhibit similar histologic sequelae, the underlying mechanisms appear to be highly heterogeneous. Therefore, it was recently proposed to redefine NAFLD to metabolic dysfunction-associated fatty liver disease (MAFLD) in which other known causes of liver disease such as alcohol consumption or viral hepatitis do not need to be excluded. Revised nomenclature envisions speeding up and facilitating anti-MAFLD drug development by means of patient stratification whereby each subgroup would benefit from distinct pharmacological interventions. As human-based in vitro research fulfils an irrefutable step in drug development, action should be taken as well in this stadium of the translational path. Indeed, most established in vitro NAFLD models rely on short-term exposure to fatty acids and use lipid accumulation as a phenotypic benchmark. This general approach to a seemingly ambiguous disease such as NAFLD therefore no longer seems applicable. Human-based in vitro models that accurately reflect distinct disease subgroups of MAFLD should thus be adopted in early preclinical disease modeling and drug testing. In this review article, we outline considerations for setting up translational in vitro experiments in the MAFLD era and allude to potential strategies to implement MAFLD heterogeneity into an in vitro setting so as to better align early drug development with future clinical trial designs.

scholarly journals In Vivo and In Vitro Models of Hepatocellular Carcinoma: Current Strategies for Translational Modeling

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5583
Author(s):  
Guilherme Ribeiro Romualdo ◽  
Kaat Leroy ◽  
Cícero Júlio Silva Costa ◽  
Gabriel Bacil Prata ◽  
Bart Vanderborght ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
In Vitro Models ◽  
Virus Infections ◽  
Alcoholic Fatty Liver ◽  
Contaminated Food ◽  
Patient Prognosis ◽  
Key Events ◽  
Translational Modeling

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third leading cause of cancer-related death globally. HCC is a complex multistep disease and usually emerges in the setting of chronic liver diseases. The molecular pathogenesis of HCC varies according to the etiology, mainly caused by chronic hepatitis B and C virus infections, chronic alcohol consumption, aflatoxin-contaminated food, and non-alcoholic fatty liver disease associated with metabolic syndrome or diabetes mellitus. The establishment of HCC models has become essential for both basic and translational research to improve our understanding of the pathophysiology and unravel new molecular drivers of this disease. The ideal model should recapitulate key events observed during hepatocarcinogenesis and HCC progression in view of establishing effective diagnostic and therapeutic strategies to be translated into clinical practice. Despite considerable efforts currently devoted to liver cancer research, only a few anti-HCC drugs are available, and patient prognosis and survival are still poor. The present paper provides a state-of-the-art overview of in vivo and in vitro models used for translational modeling of HCC with a specific focus on their key molecular hallmarks.

scholarly journals In Vitro Models for Studying Entry, Tissue Tropism, and Therapeutic Approaches of Highly Pathogenic Coronaviruses

2021 ◽  
Vol 2021 ◽  
pp. 1-21
Author(s):  
Saeid Najafi Fard ◽  
Linda Petrone ◽  
Elisa Petruccioli ◽  
Tonino Alonzi ◽  
Giulia Matusali ◽  
...  
Keyword(s):  
Rna Viruses ◽  
Current Knowledge ◽  
In Vitro Models ◽  
Cell Entry ◽  
Therapeutic Approaches ◽  
Highly Pathogenic ◽  
S Protein ◽  
Viral Attachment ◽  
The Family

Coronaviruses (CoVs) are enveloped nonsegmented positive-sense RNA viruses belonging to the family Coronaviridae that contain the largest genome among RNA viruses. Their genome encodes 4 major structural proteins, and among them, the Spike (S) protein plays a crucial role in determining the viral tropism. It mediates viral attachment to the host cell, fusion to the membranes, and cell entry using cellular proteases as activators. Several in vitro models have been developed to study the CoVs entry, pathogenesis, and possible therapeutic approaches. This article is aimed at summarizing the current knowledge about the use of relevant methodologies and cell lines permissive for CoV life cycle studies. The synthesis of this information can be useful for setting up specific experimental procedures. We also discuss different strategies for inhibiting the binding of the S protein to the cell receptors and the fusion process which may offer opportunities for therapeutic intervention.

scholarly journals α-synuclein pathogenesis in hiPSC models of Parkinson’s Disease

2021 ◽  
Author(s):  
Leo R Quinlan ◽  
Jara Maria Baena-Montes ◽  
Sahar Avazzadeh
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Modeling ◽  
Viral Vector ◽  
Neurodegenerative Disorder ◽  
Current Knowledge ◽  
Lewy Bodies ◽  
Model Systems ◽  
The Brain

α-synuclein is an increasingly prominent player in the pathology of a variety of neurodegenerative conditions. Parkinson’s disease (PD) is a neurodegenerative disorder that affects mainly the dopaminergic neurons in the substantia nigra of the brain. Typical of PD pathology is the finding of protein aggregations termed ‘Lewy bodies’ in the brain regions affected. α-synuclein is implicated in many disease states including dementia with Lewy bodies and Alzheimer’s disease. However, PD is the most common synucleinopathy and continues to be a significant focus of PD research in terms of the α-synuclein Lewy body pathology. Mutations in several genes are associated with PD development including SNCA, which encodes α-synuclein. A variety of model systems have been employed to study α-synuclein physiology and pathophysiology in an attempt to relate more closely to PD pathology. These models include cellular and animal system exploring transgenic technologies, viral vector expression and knockdown approaches, and models to study the potential prion protein-like effects of α-synuclein. The current review focuses on human induced pluripotent stem cell (iPSC) models with a specific focus on mutations or multiplications of the SNCA gene. iPSCs are a rapidly evolving technology with huge promise in the study of normal physiology and disease modeling in vitro. The ability to maintain a patient's genetic background and replicate similar cell phenotypes make iPSCs a powerful tool in the study of neurological diseases. This review focus on the current knowledge about α-synuclein physiological function as well as its role in PD pathogenesis based on human iPSC models.

scholarly journals Transcriptomic Analysis of 3D Vasculature-On-A-Chip Reveals Paracrine Factors Affecting Vasculature Growth and Maturation

2021 ◽  
Author(s):  
Angela Ruohao Wu ◽  
Sin Yen Tan ◽  
Qiuyu Jing ◽  
Ziuwin Leung ◽  
Ying Xu
Keyword(s):  
Disease Modeling ◽  
Expression Profiles ◽  
In Vitro Models ◽  
Transcriptomic Analysis ◽  
Paracrine Factors ◽  
Factors Affecting ◽  
Vascular Physiology ◽  
Versatile Technique ◽  
Vascular Mimicry

In vitro models of vasculature are of great importance for modelling vascular physiology and pathology. However, there is usually a lack of proper spatial patterning of interacting heterotypic cells in conventional vasculature dish models, which might confound results between contact and non-contact interactions. We use a microfluidic platform with structurally defined separation between human microvasculature and fibroblasts to probe their dynamic, paracrine interactions. We also develop a novel, versatile technique to retrieve cells embedded in extracellular matrix from the microfluidic device for downstream transcriptomic analysis, and uncover growth factor and cytokine expression profiles associated with improved vasculature growth. Paired receptor-ligand analysis further reveals paracrine signaling molecules that could be supplemented into the medium for vasculatures models where fibroblast co-culture is undesirable or infeasible. These findings also provide deeper insights into the molecular cues for more physiologically relevant vascular mimicry and vascularized organoid model for clinical applications such as drug screening and disease modeling.

scholarly journals Necrotizing Enterocolitis: Overview on In Vitro Models

2021 ◽  
Vol 22 (13) ◽  
pp. 6761
Author(s):  
Luigia De Fazio ◽  
Isadora Beghetti ◽  
Salvatore Nicola Bertuccio ◽  
Concetta Marsico ◽  
Silvia Martini ◽  
...  
Keyword(s):  
Necrotizing Enterocolitis ◽  
Current Knowledge ◽  
Experimental Studies ◽  
In Vitro Models ◽  
Intestinal Microbiome ◽  
Inflammatory Disorder ◽  
Intestinal Epithelial ◽  
Complex Interactions ◽  
Disease Mechanisms

Necrotizing enterocolitis (NEC) is a gut inflammatory disorder which constitutes one of the leading causes of morbidity and mortality for preterm infants. The pathophysiology of NEC is yet to be fully understood; several observational studies have led to the identification of multiple factors involved in the pathophysiology of the disease, including gut immaturity and dysbiosis of the intestinal microbiome. Given the complex interactions between microbiota, enterocytes, and immune cells, and the limited access to fetal human tissues for experimental studies, animal models have long been essential to describe NEC mechanisms. However, at present there is no animal model perfectly mimicking human NEC; furthermore, the disease mechanisms appear too complex to be studied in single-cell cultures. Thus, researchers have developed new approaches in which intestinal epithelial cells are exposed to a combination of environmental and microbial factors which can potentially trigger NEC. In addition, organoids have gained increasing attention as promising models for studying NEC development. Currently, several in vitro models have been proposed and have contributed to describe the disease in deeper detail. In this paper, we will provide an updated review of available in vitro models of NEC and an overview of current knowledge regarding its molecular underpinnings.

scholarly journals hiPSC-Derived Epidermal Keratinocytes from Ichthyosis Patients Show Altered Expression of Cornification Markers

2021 ◽  
Vol 22 (4) ◽  
pp. 1785
Author(s):  
Dulce Lima Cunha ◽  
Amanda Oram ◽  
Robert Gruber ◽  
Roswitha Plank ◽  
Arno Lingenhel ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Human Keratinocytes ◽  
In Vitro Models ◽  
Epidermal Keratinocytes ◽  
Altered Expression ◽  
Epidermal Barrier ◽  
Congenital Ichthyosis ◽  
Autosomal Recessive Congenital Ichthyosis ◽  
Induced Pluripotent

Inherited ichthyoses represent a large heterogeneous group of skin disorders characterised by impaired epidermal barrier function and disturbed cornification. Current knowledge about disease mechanisms has been uncovered mainly through the use of mouse models or human skin organotypic models. However, most mouse lines suffer from severe epidermal barrier defects causing neonatal death and human keratinocytes have very limited proliferation ability in vitro. Therefore, the development of disease models based on patient derived human induced pluripotent stem cells (hiPSCs) is highly relevant. For this purpose, we have generated hiPSCs from patients with congenital ichthyosis, either non-syndromic autosomal recessive congenital ichthyosis (ARCI) or the ichthyosis syndrome trichothiodystrophy (TTD). hiPSCs were successfully differentiated into basal keratinocyte-like cells (hiPSC-bKs), with high expression of epidermal keratins. In the presence of higher calcium concentrations, terminal differentiation of hiPSC-bKs was induced and markers KRT1 and IVL expressed. TTD1 hiPSC-bKs showed reduced expression of FLG, SPRR2B and lipoxygenase genes. ARCI hiPSC-bKs showed more severe defects, with downregulation of several cornification genes. The application of hiPSC technology to TTD1 and ARCI demonstrates the successful generation of in vitro models mimicking the disease phenotypes, proving a valuable system both for further molecular investigations and drug development for ichthyosis patients.

scholarly journals Biofabrication of advanced in vitro and ex vivo cancer models for disease modeling and drug screening

2021 ◽  
pp. FDD62
Author(s):  
Kylie G Nairon ◽  
Aleksander Skardal
Keyword(s):  
Disease Modeling ◽  
Ex Vivo ◽  
Human Tumor ◽  
In Vitro Models ◽  
Tissue Type ◽  
Organ On A Chip ◽  
Vitro Model ◽  
Model Platform ◽  
Simple Systems

Bioengineered in vitro models have advanced from 2D cultures and simple 3D cell aggregates to more complex organoids and organ-on-a-chip platforms. This shift has been substantial in cancer research; while simple systems remain in use, multi-tissue type tumor and tissue chips and patient-derived tumor organoids have grown rapidly. These more advanced models offer new tools to cancer researchers based on human tumor physiology and the potential for interactions with nontumor tissue physiology while avoiding critical differences between human and animal biology. In this focused review, the authors discuss the importance of organoid and organ-on-a-chip platforms, with a particular focus on modeling cancer, to highlight oncology-focused in vitro model platform technologies that improve upon the simple 2D cultures and 3D spheroid models of the past.

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