A perspective on human cell models for POLG-spectrum disorders: advantages and disadvantages of CRISPR-Cas-based vs. patient-derived iPSC models

2021 ◽  
Vol 33 (3) ◽  
pp. 245-249
Author(s):  
Cagla Cakmak ◽  
Hans Zempel
Keyword(s):  
Stem Cell ◽  
Human Disease ◽  
Clinical Manifestations ◽  
Model Systems ◽  
Preclinical Model ◽  
Cell Models ◽  
Therapeutic Approaches ◽  
Advantages And Disadvantages ◽  
Disease Mechanisms ◽  
Spectrum Disorders

Abstract Neurogenetic diseases represent a broad group of diseases with variable genetic causes and clinical manifestations. Among these, polymerase-gamma (POLG)-spectrum disorders are relatively frequent with an estimated disease frequency of ∼1:10.000. Also, mutations in the POLG gene are by far the most important cause for mitochondriopathy. POLG-spectrum disorders usually result in progressive loss of brain function and may involve severe and deadly encephalopathy, seizures, and neuromuscular disease, as well as cardiac and hepatic failure in some cases. Onset of disease may range from birth to late adulthood, and disease duration ranges from weeks in severe cases to decades. There is no curative treatment; current animal models do not faithfully recapitulate human disease, complicating preclinical therapeutic studies. Human-based preclinical model systems must be developed to understand the human disease mechanisms and develop therapeutic approaches. In this review, we provide an overview of the current approaches to model neurogenetic disorders in a human cellular and neuronal environment with a focus on POLG-spectrum disorders. We discuss the necessity of using neuronal cells and the advantages and pitfalls of currently available cell model approaches, namely (i) CRISPR-based (i. e., genetically engineered) and induced pluripotent stem cell (iPSC) (i. e., stem cell like)-derived neuronal models and (ii) the reprogramming of patient-derived cells into iPSCs and derived neurons. Despite the fact that cell models are by definition in vitro systems incapable of recapitulating all aspects of human disease, they are still the reasonable point of start to discover disease mechanisms and develop therapeutic approaches to treat neurogenetic diseases.

Atypical Cellular Disorders

Hematology ◽  
2002 ◽  
Vol 2002 (1) ◽  
pp. 297-314 ◽  
Author(s):  
Robert J. Arceci ◽  
B. Jack Longley ◽  
Peter D. Emanuel
Keyword(s):  
Targeted Therapies ◽  
Clinical Manifestations ◽  
Model Systems ◽  
Therapeutic Approaches ◽  
New Therapeutic Approaches ◽  
Disease Mechanisms ◽  
Myeloproliferative Syndrome ◽  
Kit Receptor ◽  
And Function ◽  
Clinical Problems

Abstract Atypical cellular disorders are commonly considered part of the gray zone linking oncology to hematology and immunology. Although these disorders are relatively uncommon, they often represent significant clinical problems, provide an opportunity to understand basic disease mechanisms, and serve as model systems for the development of novel targeted therapies. This chapter focuses on such disorders. In Section I, Dr. Arceci discusses the pathogenesis of Langerhans cell histiocytosis (LCH) in terms of the hypothesis that this disorder represents an atypical myeloproliferative syndrome. The clinical manifestations and treatment of LCH in children and adults is discussed along with possible future therapeutic approaches based upon biological considerations. In Section II, Dr. Longley considers the molecular changes in the c-Kit receptor that form the basis of mastocytosis. Based on the location and function of c-Kit mutations, he develops a paradigm for the development of specific, targeted therapies. In Section III, Dr. Emanuel provides a review of the “mixed myeloproliferative and myelodysplastic disorders,” including novel therapeutic approaches based on aberrant pathogenetic mechanisms. Taken together, these chapters should provide an overview of the biological basis for these disorders, their clinical manifestations, and new therapeutic approaches

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.

scholarly journals A Yeast-Based Model for Hereditary Motor and Sensory Neuropathies: A Simple System for Complex, Heterogeneous Diseases

2020 ◽  
Vol 21 (12) ◽  
pp. 4277 ◽  
Author(s):  
Weronika Rzepnikowska ◽  
Joanna Kaminska ◽  
Dagmara Kabzińska ◽  
Katarzyna Binięda ◽  
Andrzej Kochański
Keyword(s):  
Molecular Mechanisms ◽  
Genetic Diagnosis ◽  
Clinical Manifestations ◽  
Model System ◽  
Research Field ◽  
Therapeutic Approaches ◽  
Rare Disorders ◽  
Advantages And Disadvantages ◽  
Pathogenic Variants ◽  
Disease Subtypes

Charcot–Marie–Tooth (CMT) disease encompasses a group of rare disorders that are characterized by similar clinical manifestations and a high genetic heterogeneity. Such excessive diversity presents many problems. Firstly, it makes a proper genetic diagnosis much more difficult and, even when using the most advanced tools, does not guarantee that the cause of the disease will be revealed. Secondly, the molecular mechanisms underlying the observed symptoms are extremely diverse and are probably different for most of the disease subtypes. Finally, there is no possibility of finding one efficient cure for all, or even the majority of CMT diseases. Every subtype of CMT needs an individual approach backed up by its own research field. Thus, it is little surprise that our knowledge of CMT disease as a whole is selective and therapeutic approaches are limited. There is an urgent need to develop new CMT models to fill the gaps. In this review, we discuss the advantages and disadvantages of yeast as a model system in which to study CMT diseases. We show how this single-cell organism may be used to discriminate between pathogenic variants, to uncover the mechanism of pathogenesis, and to discover new therapies for CMT disease.

scholarly journals An Integrated Approach to Studying Rare Neuromuscular Diseases Using Animal and Human Cell-Based Models

2022 ◽  
Vol 9 ◽  
Author(s):  
Timothy J. Hines ◽  
Cathleen Lutz ◽  
Stephen A. Murray ◽  
Robert W. Burgess
Keyword(s):  
Human Disease ◽  
Neuromuscular Diseases ◽  
Trna Synthetase ◽  
Genetically Engineered ◽  
Model Systems ◽  
Model Organisms ◽  
Cellular Mechanisms ◽  
Disease Mechanisms

As sequencing technology improves, the identification of new disease-associated genes and new alleles of known genes is rapidly increasing our understanding of the genetic underpinnings of rare diseases, including neuromuscular diseases. However, precisely because these disorders are rare and often heterogeneous, they are difficult to study in patient populations. In parallel, our ability to engineer the genomes of model organisms, such as mice or rats, has gotten increasingly efficient through techniques such as CRISPR/Cas9 genome editing, allowing the creation of precision human disease models. Such in vivo model systems provide an efficient means for exploring disease mechanisms and identifying therapeutic strategies. Furthermore, animal models provide a platform for preclinical studies to test the efficacy of those strategies. Determining whether the same mechanisms are involved in the human disease and confirming relevant parameters for treatment ideally involves a human experimental system. One system currently being used is induced pluripotent stem cells (iPSCs), which can then be differentiated into the relevant cell type(s) for in vitro confirmation of disease mechanisms and variables such as target engagement. Here we provide a demonstration of these approaches using the example of tRNA-synthetase-associated inherited peripheral neuropathies, rare forms of Charcot-Marie-Tooth disease (CMT). Mouse models have led to a better understanding of both the genetic and cellular mechanisms underlying the disease. To determine if the mechanisms are similar in human cells, we will use genetically engineered iPSC-based models. This will allow comparisons of different CMT-associated GARS alleles in the same genetic background, reducing the variability found between patient samples and simplifying the availability of cell-based models for a rare disease. The necessity of integrating mouse and human models, strategies for accomplishing this integration, and the challenges of doing it at scale are discussed using recently published work detailing the cellular mechanisms underlying GARS-associated CMT as a framework.

scholarly journals Cell Models and Omics Techniques for the Study of Nonalcoholic Fatty Liver Disease: Focusing on Stem Cell-Derived Cell Models

Antioxidants ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 86
Author(s):  
María Pelechá ◽  
Estela Villanueva-Bádenas ◽  
Enrique Timor-López ◽  
María Teresa Donato ◽  
Laia Tolosa
Keyword(s):  
Stem Cell ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Molecular Mechanisms ◽  
Cell Models ◽  
Nonalcoholic Fatty Liver ◽  
Advantages And Disadvantages

Nonalcoholic fatty liver disease (NAFLD) is now the leading cause of chronic liver disease in western countries. The molecular mechanisms leading to NAFLD are only partially understood, and effective therapeutic interventions are clearly needed. Therefore, preclinical research is required to improve knowledge about NAFLD physiopathology and to identify new therapeutic targets. Primary human hepatocytes, human hepatic cell lines, and human stem cell-derived hepatocyte-like cells exhibit different hepatic phenotypes and have been widely used for studying NAFLD pathogenesis. In this paper, apart from employing the different in vitro cell models for the in vitro assessment of NAFLD, we also reviewed other approaches (metabolomics, transcriptomics, and high-content screening). We aimed to summarize the characteristics of different cell types and methods and to discuss their major advantages and disadvantages for NAFLD modeling.

scholarly journals Emerging Therapeutic Strategies for Limbal Stem Cell Deficiency

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Ying Dong ◽  
Han Peng ◽  
Robert M. Lavker
Keyword(s):  
Stem Cell ◽  
Corneal Epithelium ◽  
Ocular Surface ◽  
Limbal Stem Cell Deficiency ◽  
Current Status ◽  
Epithelial Stem Cells ◽  
Therapeutic Approaches ◽  
Advantages And Disadvantages ◽  
Limbal Stem Cell ◽  
Novel Therapeutic

Identification and characterization of the limbal epithelial stem cells (LESCs) has proven to be a major accomplishment in anterior ocular surface biology. These cells have been shown to be a subpopulation of limbal epithelial basal cells, which serve as the progenitor population of the corneal epithelium. LESCs have been demonstrated to play an important role in maintaining corneal epithelium homeostasis. Many ocular surface diseases, including intrinsic (e.g., Sjogren’s syndrome) or extrinsic (e.g., alkali or thermal burns) insults, which impair LESCs, can lead to limbal stem cell deficiency (LSCD). LSCD is characterized by an overgrowth of conjunctival-derived epithelial cells, corneal neovascularization, and chronic inflammation, eventually leading to blindness. Treatment of LSCD has been challenging, especially in bilateral total LSCD. Recently, advances in LESC research have led to novel therapeutic approaches for treating LSCD, such as transplantation of the cultured limbal epithelium. These novel therapeutic approaches have demonstrated efficacy for ocular surface reconstruction and restoration of vision in patients with LSCD. However, they all have their own limitations. Here, we describe the current status of LSCD treatment and discuss the advantages and disadvantages of the available therapeutic modalities.

Investigating human disease using stem cell models

2014 ◽  
Vol 15 (9) ◽  
pp. 625-639 ◽  
Author(s):  
Jared L. Sterneckert ◽  
Peter Reinhardt ◽  
Hans R. Schöler
Keyword(s):  
Stem Cell ◽  
Human Disease ◽  
Cell Models ◽  
Stem Cell Models

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.

Sign in / Sign up

Export Citation Format

Share Document