scholarly journals Role of SHH in Patterning Human Pluripotent Cells towards Ventral Forebrain Fates

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 914
Author(s):  
Melanie V. Brady ◽  
Flora M. Vaccarino
Keyword(s):  
Stem Cell ◽  
Human Brain ◽  
Human Development ◽  
Disease Modeling ◽  
Model Systems ◽  
Advantages And Disadvantages ◽  
Technical Ability ◽  
Cellular Phenotypes

The complexities of human neurodevelopment have historically been challenging to decipher but continue to be of great interest in the contexts of healthy neurobiology and disease. The classic animal models and monolayer in vitro systems have limited the types of questions scientists can strive to answer in addition to the technical ability to answer them. However, the tridimensional human stem cell-derived organoid system provides the unique opportunity to model human development and mimic the diverse cellular composition of human organs. This strategy is adaptable and malleable, and these neural organoids possess the morphogenic sensitivity to be patterned in various ways to generate the different regions of the human brain. Furthermore, recapitulating human development provides a platform for disease modeling. One master regulator of human neurodevelopment in many regions of the human brain is sonic hedgehog (SHH), whose expression gradient and pathway activation are responsible for conferring ventral identity and shaping cellular phenotypes throughout the neural axis. This review first discusses the benefits, challenges, and limitations of using organoids for studying human neurodevelopment and disease, comparing advantages and disadvantages with other in vivo and in vitro model systems. Next, we explore the range of control that SHH exhibits on human neurodevelopment, and the application of SHH to various stem cell methodologies, including organoids, to expand our understanding of human development and disease. We outline how this strategy will eventually bring us much closer to uncovering the intricacies of human neurodevelopment and biology.

Constructing stem cell microenvironments using bioengineering approaches

2013 ◽  
Vol 45 (23) ◽  
pp. 1123-1135 ◽  
Author(s):  
David A. Brafman
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Disease Modeling ◽  
Mechanical Stimuli ◽  
Culture Methods ◽  
Stem Cell Fate ◽  
And Function

Within the adult organism, stem cells reside in defined anatomical microenvironments called niches. These architecturally diverse microenvironments serve to balance stem cell self-renewal and differentiation. Proper regulation of this balance is instrumental to tissue repair and homeostasis, and any imbalance can potentially lead to diseases such as cancer. Within each of these microenvironments, a myriad of chemical and physical stimuli interact in a complex (synergistic or antagonistic) manner to tightly regulate stem cell fate. The in vitro replication of these in vivo microenvironments will be necessary for the application of stem cells for disease modeling, drug discovery, and regenerative medicine purposes. However, traditional reductionist approaches have only led to the generation of cell culture methods that poorly recapitulate the in vivo microenvironment. To that end, novel engineering and systems biology approaches have allowed for the investigation of the biological and mechanical stimuli that govern stem cell fate. In this review, the application of these technologies for the dissection of stem cell microenvironments will be analyzed. Moreover, the use of these engineering approaches to construct in vitro stem cell microenvironments that precisely control stem cell fate and function will be reviewed. Finally, the emerging trend of using high-throughput, combinatorial methods for the stepwise engineering of stem cell microenvironments will be explored.

scholarly journals TMOD-12. THE ROLE OF INTEGRIN α V AND CD44 IN GBM MIGRATION USING HUMAN ORGANOTYPIC SLICES

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi265-vi265
Author(s):  
Zev Binder ◽  
Sarah Hyun Ji Kim ◽  
Pei-Hsun Wu ◽  
Anjil Giri ◽  
Gary Gallia ◽  
...  
Keyword(s):  
Human Brain ◽  
Cell Motility ◽  
Brain Tissue ◽  
Brain Slices ◽  
Model System ◽  
Model Systems ◽  
In Vivo Model ◽  
Human Brain Tissue

Abstract Current model systems used for GBM research include traditional in vitro cell line-based assays and in vivo animal studies. In vitro model systems offer the advantages of being easy to use, relatively inexpensive, and fast growing. However, these models lack key elements of the pathology they are attempting to model, including the biochemical and biophysical microenvironment and three-dimensional structure inherent to human brain tissue. In vivo model systems address these limitations, but have restrictions of their own. Species differences may result in non-applicable results and animal experiments are often not designed like clinical trials. Evidence of the limitations of current GBM models is found in the disparity between basic research findings and successful new treatments for GBMs in the clinic. Here we present an alternative model system for the study of human GBM cell motility and invasion, which features advantages of both in vitro and in vivo model systems. Using human organotypic brain slices as scaffolding for tumor growth, we explored the dynamic process of GBM cell invasion within human brain tissue. To demonstrate the utility of the model system, we investigated the effects of depletion of integrin α V (ITGAV) and CD44 on GBM cell motility. These two cell-surface proteins have been identified to have key functions in GBM cell motility. However, knockdown of ITGAV had little effect on tumor cell motility in organotypics while CD44 knockdown significantly reduced cell movement. Finally, we compare motility results from cells in human brain slices to those from cells growing on standard Matrigel and in mouse brain organotypics. We found significant differences in motility depending on the substrate in which the cells were moving. Our findings highlight the physiologic characteristics of human brain organotypics and demonstrate the use of real-time imaging in the ex vivo system.

scholarly journals Stem Cell-Based Disease Models for Inborn Errors of Immunity

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 108
Author(s):  
Aline Zbinden ◽  
Kirsten Canté-Barrett ◽  
Karin Pike-Overzet ◽  
Frank J. T. Staal
Keyword(s):  
Stem Cell ◽  
Disease Modeling ◽  
Induced Pluripotent Stem Cell ◽  
Disease Models ◽  
Inborn Errors ◽  
Hematopoietic Stem ◽  
Inborn Errors Of Immunity ◽  
Induced Pluripotent

The intrinsic capacity of human hematopoietic stem cells (hHSCs) to reconstitute myeloid and lymphoid lineages combined with their self-renewal capacity hold enormous promises for gene therapy as a viable treatment option for a number of immune-mediated diseases, most prominently for inborn errors of immunity (IEI). The current development of such therapies relies on disease models, both in vitro and in vivo, which allow the study of human pathophysiology in great detail. Here, we discuss the current challenges with regards to developmental origin, heterogeneity and the subsequent implications for disease modeling. We review models based on induced pluripotent stem cell technology and those relaying on use of adult hHSCs. We critically review the advantages and limitations of current models for IEI both in vitro and in vivo. We conclude that existing and future stem cell-based models are necessary tools for developing next generation therapies for IEI.

scholarly journals Author Correction: The promise(s) of mesenchymal stem cell therapy in averting preclinical diabetes: lessons from in vivo and in vitro model systems

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nagasuryaprasad Kotikalapudi ◽  
Samuel Joshua Pragasam Sampath ◽  
Sinha Sukesh Narayan ◽  
Bhonde R. ◽  
Harishankar Nemani ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Cell Therapy ◽  
In Vitro Model ◽  
Model Systems ◽  
Mesenchymal Stem Cell Therapy ◽  
Preclinical Diabetes ◽  
Vitro Model

Neural microphysiological systems for in vitro modeling of peripheral nervous system disorders

2019 ◽  
Vol 2 (2) ◽  
pp. 101-117 ◽  
Author(s):  
Kevin J Pollard ◽  
Anup D Sharma ◽  
Michael J Moore
Keyword(s):  
High Throughput ◽  
Disease Modeling ◽  
Model Systems ◽  
Nerve Tissue ◽  
Autonomic Nerve ◽  
Metabolic Dysfunction ◽  
Nerve Structure ◽  
Hereditary Disorders

PNS disease pathology is diverse and underappreciated. Peripheral neuropathy may result in sensory, motor or autonomic nerve dysfunction and can be induced by metabolic dysfunction, inflammatory dysfunction, cytotoxic pharmaceuticals, rare hereditary disorders or may be idiopathic. Current preclinical PNS disease research relies heavily on the use of rodent models. In vivo methods are effective but too time-consuming and expensive for high-throughput experimentation. Conventional in vitro methods can be performed with high throughput but lack the biological complexity necessary to directly model in vivo nerve structure and function. In this review, we survey in vitro PNS model systems and propose that 3D-bioengineered microphysiological nerve tissue can improve in vitro–in vivo extrapolation and expand the capabilities of in vitro PNS disease modeling.

scholarly journals Advances in Modeling the Immune Microenvironment of Colorectal Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Paul Sukwoo Yoon ◽  
Nuala Del Piccolo ◽  
Venktesh S. Shirure ◽  
Yushuan Peng ◽  
Amanda Kirane ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
3D Culture ◽  
Model Systems ◽  
Preclinical Model ◽  
Advantages And Disadvantages ◽  
Culture Models

Colorectal cancer (CRC) is the third most common cancer and second leading cause of cancer-related death in the US. CRC frequently metastasizes to the liver and these patients have a particularly poor prognosis. The infiltration of immune cells into CRC tumors and liver metastases accurately predicts disease progression and patient survival. Despite the evident influence of immune cells in the CRC tumor microenvironment (TME), efforts to identify immunotherapies for CRC patients have been limited. Here, we argue that preclinical model systems that recapitulate key features of the tumor microenvironment—including tumor, stromal, and immune cells; the extracellular matrix; and the vasculature—are crucial for studies of immunity in the CRC TME and the utility of immunotherapies for CRC patients. We briefly review the discoveries, advantages, and disadvantages of current in vitro and in vivo model systems, including 2D cell culture models, 3D culture systems, murine models, and organ-on-a-chip technologies.

scholarly journals The Use of Stem Cell-Derived Organoids in Disease Modeling: An Update

2021 ◽  
Vol 22 (14) ◽  
pp. 7667
Author(s):  
Joseph Azar ◽  
Hisham F. Bahmad ◽  
Darine Daher ◽  
Maya M. Moubarak ◽  
Ola Hadadeh ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Disease Modeling ◽  
New Technology ◽  
Three Dimensional ◽  
Cell Types ◽  
Clinical Applications ◽  
In Vitro Drug Screening

Organoids represent one of the most important advancements in the field of stem cells during the past decade. They are three-dimensional in vitro culturing models that originate from self-organizing stem cells and can mimic the in vivo structural and functional specificities of body organs. Organoids have been established from multiple adult tissues as well as pluripotent stem cells and have recently become a powerful tool for studying development and diseases in vitro, drug screening, and host–microbe interaction. The use of stem cells—that have self-renewal capacity to proliferate and differentiate into specialized cell types—for organoids culturing represents a major advancement in biomedical research. Indeed, this new technology has a great potential to be used in a multitude of fields, including cancer research, hereditary and infectious diseases. Nevertheless, organoid culturing is still rife with many challenges, not limited to being costly and time consuming, having variable rates of efficiency in generation and maintenance, genetic stability, and clinical applications. In this review, we aim to provide a synopsis of pluripotent stem cell-derived organoids and their use for disease modeling and other clinical applications.

scholarly journals The promise(s) of mesenchymal stem cell therapy in averting preclinical diabetes: lessons from in vivo and in vitro model systems

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nagasuryaprasad Kotikalapudi ◽  
Samuel Joshua Pragasam Sampath ◽  
Sinha Sukesh Narayan ◽  
Bhonde Ramesh R ◽  
Harishankar Nemani ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Clinical Success ◽  
Significant Risk ◽  
Stromal Vascular Fraction ◽  
Significant Risk Factor ◽  
Model Systems ◽  
Mesenchymal Stem Cell Therapy

AbstractObesity (Ob) poses a significant risk factor for the onset of metabolic syndrome with associated complications, wherein the Mesenchymal Stem Cell (MSC) therapy shows pre-clinical success. Here, we explore the therapeutic applications of human Placental MSCs (P-MSCs) to address Ob-associated Insulin Resistance (IR) and its complications. In the present study, we show that intramuscular injection of P-MSCs homed more towards the visceral site, restored HOMA-IR and glucose homeostasis in the WNIN/GR-Ob (Ob-T2D) rats. P-MSC therapy was effective in re-establishing the dysregulated cytokines. We report that the P-MSCs activates PI3K-Akt signaling and regulates the Glut4-dependant glucose uptake and its utilization in WNIN/GR-Ob (Ob-T2D) rats compared to its control. Our data reinstates P-MSC treatment's potent application to alleviate IR and restores peripheral blood glucose clearance evidenced in stromal vascular fraction (SVF) derived from white adipose tissue (WAT) of the WNIN/GR-Ob rats. Gaining insights, we show the activation of the PI3K-Akt pathway by P-MSCs both in vivo and in vitro (palmitate primed 3T3-L1 cells) to restore the insulin sensitivity dysregulated adipocytes. Our findings suggest a potent application of P-MSCs in  pre-clinical/Ob-T2D management.

scholarly journals Differentiation, Evaluation, and Application of Human Induced Pluripotent Stem Cell–Derived Endothelial Cells

2017 ◽  
Vol 37 (11) ◽  
pp. 2014-2025 ◽  
Author(s):  
Yang Lin ◽  
Chang-Hyun Gil ◽  
Mervin C. Yoder
Keyword(s):  
Endothelial Cells ◽  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Disease Modeling ◽  
Induced Pluripotent Stem Cell ◽  
Patient Specific ◽  
Induced Pluripotent ◽  
Human Ipsc

The emergence of induced pluripotent stem cell (iPSC) technology paves the way to generate large numbers of patient-specific endothelial cells (ECs) that can be potentially delivered for regenerative medicine in patients with cardiovascular disease. In the last decade, numerous protocols that differentiate EC from iPSC have been developed by many groups. In this review, we will discuss several common strategies that have been optimized for human iPSC-EC differentiation and subsequent studies that have evaluated the potential of human iPSC-EC as a cell therapy or as a tool in disease modeling. In addition, we will emphasize the importance of using in vivo vessel-forming ability and in vitro clonogenic colony–forming potential as a gold standard with which to evaluate the quality of human iPSC-EC derived from various protocols.

scholarly journals Modeling Host-Virus Interactions in Viral Infectious Diseases Using Stem-Cell-Derived Systems and CRISPR/Cas9 Technology

Viruses ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 124 ◽  
Author(s):  
Jihoon Kim ◽  
Bon-Kyoung Koo ◽  
Ki-Jun Yoon
Keyword(s):  
Stem Cell ◽  
Viral Infections ◽  
Adult Stem Cell ◽  
Viral Pathogenesis ◽  
Extensive Study ◽  
Model Systems ◽  
Host Virus Interactions ◽  
Virus Interactions

Pathologies induced by viral infections have undergone extensive study, with traditional model systems such as two-dimensional (2D) cell cultures and in vivo mouse models contributing greatly to our understanding of host-virus interactions. However, the technical limitations inherent in these systems have constrained efforts to more fully understand such interactions, leading to a search for alternative in vitro systems that accurately recreate in vivo physiology in order to advance the study of viral pathogenesis. Over the last decade, there have been significant technological advances that have allowed researchers to more accurately model the host environment when modeling viral pathogenesis in vitro, including induced pluripotent stem cells (iPSCs), adult stem-cell-derived organoid culture systems and CRISPR/Cas9-mediated genome editing. Such technological breakthroughs have ushered in a new era in the field of viral pathogenesis, where previously challenging questions have begun to be tackled. These include genome-wide analysis of host-virus crosstalk, identification of host factors critical for viral pathogenesis, and the study of viral pathogens that previously lacked a suitable platform, e.g., noroviruses, rotaviruses, enteroviruses, adenoviruses, and Zika virus. In this review, we will discuss recent advances in the study of viral pathogenesis and host-virus crosstalk arising from the use of iPSC, organoid, and CRISPR/Cas9 technologies.

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