Review
Cell Biology
Mario G. Pavez-Giani, Lukas Cyganek
Summary: This review summarizes recent advances in iPSC-based disease modeling of mitochondrial cardiomyopathies and explores the patho-mechanistic insights as well as new therapeutic approaches. Researchers have used iPSC technology to recapitulate major characteristics of mitochondrial cardiomyopathies, providing a powerful platform for drug development and testing of new therapies.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Review
Cell Biology
Hidenori Tani, Shugo Tohyama
Summary: The emergence of human induced pluripotent stem cells (hiPSCs) and efficient differentiation of hiPSC-derived cardiomyocytes (hiPSC-CMs) have the potential to replicate the features of the human heart. Although the immaturity of hiPSC-CMs poses a challenge, various strategies have been effective in promoting maturation. Three-dimensional cardiac models and disease models using patient-specific hiPSC-CMs have enhanced our understanding of cardiac diseases and therapies. Besides disease mechanisms and drug responses, hiPSC-CMs can also be used for drug evaluation and predicting drug risk. This review discusses the current strategies and future applications of hiPSC-CMs for disease modeling, drug development, clinical trials, and cardiotoxicity tests.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Review
Cell Biology
Juan Huang, Qi Feng, Li Wang, Bingying Zhou
Summary: Cardiac diseases are the leading cause of global mortality, but limited progress has been made in developing therapeutic options. The use of animal models has limitations due to species-specific differences, leading to inaccurate drug testing results. Human pluripotent stem cell (hPSC) technology offers promising alternatives for heart disease modeling, cell therapy, and drug discovery, with potential for revolutionizing these fields with further optimization required.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Review
Cell Biology
Noemie Berenger-Currias, Cecile Martinat, Sandrine Baghdoyan
Summary: DM1 is a progressive multisystemic disease caused by the expansion of a CTG repeat tract in the DMPK gene. Different in vitro models, especially human pluripotent stem cell-based models, have significantly contributed to the understanding of DM1 mechanism and development of new therapeutic approaches. These models have led to phase III clinical trials for DM1 treatment.
Review
Chemistry, Multidisciplinary
Lin-hui Zhai, Kai-feng Chen, Bing-bing Hao, Min-jia Tan
Summary: Protein post-translational modifications (PTMs) are crucial for protein activity regulation and are involved in diseases. PTM regulatory enzymes are important drug targets. Mass spectrometry-based proteomics enables systematic characterization of PTMs for drug target identification, mechanism elucidation and biomarker discovery in personalized therapy.
ACTA PHARMACOLOGICA SINICA
(2022)
Review
Cell Biology
Rie Ouchi, Hiroyuki Koike
Summary: The discovery of human pluripotent stem cells (PSCs), including embryonic stem cells and induced pluripotent stem cells (iPSCs), has greatly advanced our understanding of human developmental biology and has been used in drug discovery and disease treatments. PSC-derived organoids, which replicate the complex structures of living organs, have been created and used in various fields. iPSC-derived organoids, with their genetic background matching the donor, are useful for disease modeling, pathophysiology elucidation, and drug screening. They are also promising in regenerative medicine as a low-risk alternative to organ transplantation.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2023)
Article
Materials Science, Biomaterials
Yoshiki Nakashima, Shinsuke Yoshida, Masayoshi Tsukahara
Summary: Previous belief regarding the compatibility of human induced pluripotent stem cells (hiPSCs) and the coating material Laminin 221 has been challenged by this study. It was found that hiPSCs derived from human mononuclear cells can form peninsular-like colonies when cultured on Laminin 221, and these colonies can be passaged multiple times. The expression of undifferentiated markers tends to be higher in hiPSCs cultured on Laminin 221, and these cells also showed the ability to differentiate into cardiomyocytes on Laminin 221.
REGENERATIVE BIOMATERIALS
(2022)
Review
Cell Biology
Raj Bose, Soumyabrata Banerjee, Gary L. Dunbar
Summary: Brain organoids are important in vitro tools for modeling various aspects of brain development and disorders, providing insights into the molecular mechanisms involved in neurological diseases. Models derived from induced pluripotent stem cells (iPSCs), including 2D, 3D, and blood-brain barrier models, have advantages in disease modeling and can be used to develop vascularized and functional 3D models of brain processes. The applications of brain organoids for modeling major neurodegenerative diseases and neurodevelopmental disorders are also explored in this review.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Review
Oncology
Tatiana R. Perry, Michelle L. Roberts, Bipin Sunkara, Ragasnehith Maddula, Tyson McLeish, Jose Gomez, Julliette Lucas, David Rayan, Sahishnu Patel, Mingyu Liang, Zeljko J. Bosnjak, Sherry-Ann Brown
Summary: This review explores the cardiovascular toxicity of common cancer therapeutic agents and emphasizes the significance of studying cardiomyocytes derived from human-induced pluripotent stem cells. It highlights the potential of personalized precision cardio-oncology in reducing cardiovascular toxicity through individualized treatment plans.
CURRENT ONCOLOGY REPORTS
(2021)
Review
Biochemistry & Molecular Biology
Dario Melgari, Serena Calamaio, Anthony Frosio, Rachele Prevostini, Luigi Anastasia, Carlo Pappone, Ilaria Rivolta
Summary: The development of high-throughput automated patch-clamp technology is a recent breakthrough in Brugada syndrome research. This technology, combined with the use of patient-derived cardiomyocytes, has greatly improved our understanding of the underlying mechanisms of this condition and led to the development of more effective treatments for cardiovascular diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Cardiac & Cardiovascular Systems
Parisa K. Kargaran, Diogo Mosqueira, Tamas Kozicz
Summary: Mitochondrial medicine is a rapidly evolving field with implications in neurodegenerative diseases, type 2 diabetes, aging, and cardiovascular disorders. Effective treatments for mitochondrial diseases are currently lacking, highlighting the need for developing platforms to target the mitochondrial genome. iPSC-CM models and cellular models offer promising avenues for discovering and testing new therapies for mitochondrial diseases.
FRONTIERS IN CARDIOVASCULAR MEDICINE
(2021)
Review
Chemistry, Medicinal
Xiying Lin, Jiayu Tang, Yan-Ru Lou
Summary: Human pluripotent stem cell-derived in vitro models play an active role in drug discovery and development, assisting in phenotypic and target-based screening, target validation, toxicology evaluation, precision medicine, and clinical trials, ultimately improving the success rate of drug discovery and development.
Review
Cell Biology
Alexandra Benchoua, Marie Lasbareilles, Johana Tournois
Summary: Advances in human pluripotent stem cell biology have allowed for the creation of patient-specific human neurons, which provide unprecedented opportunities for investigating disease mechanisms and discovering new therapeutic strategies. These models help in identifying new molecular or functional targets for drug discovery and designing novel pharmacological approaches for rare genetic disorders, neurodegenerative diseases, and psychiatric disorders.
Review
Biochemistry & Molecular Biology
Ana Rita Gomes, Tiago G. Fernandes, Joaquim M. S. Cabral, Maria Margarida Diogo
Summary: Rett syndrome is a neurodevelopmental disorder caused by mutations in the MeCP2 gene, highlighting the importance of studying MeCP2 and its regulated targets for understanding disease mechanisms. Research using human pluripotent stem cells has contributed significantly to Rett syndrome studies.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biotechnology & Applied Microbiology
Boram Son, Hyungro Yoon, Jina Ryu, Haein Lee, Jinmyoung Joo, Hee Ho Park, Tai Hyun Park
Summary: This study aimed to improve the efficiency of human iPSC generation by introducing the reprogramming factor Lin28. The researchers used a soluble Lin28-30Kc19 fusion protein to deliver Lin28 into the cells, resulting in an increased number and size of generated AP-positive hiPSC colonies. This recombinant protein could potentially be used as a valuable material for enhancing hiPSC generation efficiency and as an alternative to conventional methods.
FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY
(2022)
Review
Neurosciences
Benjamin E. Clarke, Doaa M. Taha, Giulia E. Tyzack, Rickie Patani
Summary: Increasing evidence suggests that astrocytes exhibit functional heterogeneity in different brain regions, with their diversity determining a spectrum of physiological states. They are now seen as viable targets for therapies aiming to restore neural circuit integrity in neurodegenerative disorders, and understanding their physiology and functional diversity will guide therapeutic strategies in these diseases.
Review
Neurosciences
Hannah Franklin, Benjamin E. Clarke, Rickie Patani
Summary: Astrocytes and microglia play critical roles in maintaining homeostasis and immune functions in the healthy central nervous system, with dysfunction implicated in various neurodegenerative diseases. Human in vitro models offer unique insights into disease biology by providing a manipulable model system directly from patients.
PROGRESS IN NEUROBIOLOGY
(2021)
Article
Clinical Neurology
Doaa M. Taha, Benjamin E. Clarke, Claire E. Hall, Giulia E. Tyzack, Oliver J. Ziff, Linda Greensmith, Bernadett Kalmar, Mhoriam Ahmed, Aftab Alam, Eric P. Thelin, Nuria Marco Garcia, Adel Helmy, Christopher R. Sibley, Rickie Patani
Summary: This study investigates the cellular autonomy and uniformity of astrocyte reactive transformation in different genetic forms of amyotrophic lateral sclerosis. By using enriched and human induced pluripotent stem cell-derived astrocytes from patients with VCP and SOD1 mutations, the study shows that reactive transformation can occur cell-autonomously in ALS astrocytes and there is molecular and functional heterogeneity between different disease-causing mutations.
Article
Biochemistry & Molecular Biology
Oliver J. Ziff, Benjamin E. Clarke, Doaa M. Taha, Hamish Crerar, Nicholas M. Luscombe, Rickie Patani
Summary: This study reveals that astrocytes in amyotrophic lateral sclerosis (ALS) exhibit inflammatory reactive features and suppress neuronal support mechanisms. These findings offer potential therapeutic targets for ALS.
Article
Clinical Neurology
Colombine Verzat, Jasmine Harley, Rickie Patani, Raphaeelle Luisier
Summary: Our study revealed various ALS-related morphological changes through deep learning imaging methods, uncovering underappreciated disease-relevant information in both generic and specific fluorescent markers. This establishes the use of image-based deep learning for rapid, automated, and unbiased identification of biological hypotheses.
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
(2022)
Article
Engineering, Biomedical
Cathleen Hagemann, Carmen Moreno Gonzalez, Ludovica Guetta, Giulia Tyzack, Ciro Chiappini, Andrea Legati, Rickie Patani, Andrea Serio
Summary: Stem cell-based experimental platforms in neuroscience can effectively mimic key aspects of human development and disease. However, conventional culture systems may not accurately represent the engineering constraints faced by cells in vivo, especially for neurons with long axons like spinal motor neurons. The establishment of a bioengineered platform to assemble arrays of human axons of various lengths has revealed a link between axon length and metabolism in human motor neurons, shedding light on a length-dependent mechanism that influences homeostatic processes within these cells. These findings have important implications for modeling neurodegenerative disorders in vitro and emphasize the importance of accurately modeling cell shape and biophysical constraints in experimental settings.
ADVANCED HEALTHCARE MATERIALS
(2022)
Article
Biochemistry & Molecular Biology
Marija Petric Howe, Hamish Crerar, Jacob Neeves, Jasmine Harley, Giulia E. Tyzack, Pierre Klein, Andres Ramos, Rickie Patani, Raphaelle Luisier
Summary: Intron retention is an important splicing event during motor neuron development. Cytoplasmic intron-retaining transcripts (IRTs) show high RNA-binding protein and miRNA occupancy. ALS-causing VCP mutations lead to an increase in cytoplasmic abundance of a specific class of IRTs, coinciding with an increase in the nuclear expression level of predicted miRNA target genes.
Review
Chemistry, Medicinal
Jessica Merjane, Roger Chung, Rickie Patani, Leszek Lisowski
Summary: Despite the mysterious etiology, differentiated treatments are required for ALS to address both familial and sporadic cases. Targeting mechanisms of defective protein homeostasis and RNA processing, as well as exploring the use of gene therapy through adeno-associated virus (AAV) for gene delivery to the CNS, might provide potential therapeutic interventions. Overall, there is a strong need for disease modifying treatments for ALS that can effectively treat the full spectrum of cases.
MEDICINAL RESEARCH REVIEWS
(2023)
Review
Clinical Neurology
Rickie Patani, Giles E. Hardingham, Shane A. Liddelow
Summary: Therapies that prevent neuronal loss in neuroinflammation and neurodegenerative disease are still elusive. This review highlights the importance of 'omics' technologies in characterizing the functional states of reactive astrocytes in different pathological scenarios.
NATURE REVIEWS NEUROLOGY
(2023)
Article
Clinical Neurology
Christy Hung, Rickie Patani
Summary: This study uses a patient-derived stem cell model to uncover disease mechanisms in a type of dementia closely related to motor neuron disease called FTD. Specifically, they show that the increase of a particular type of tau protein-called the 4R isoform-drives degeneration of nerve cells, thereby causing the disease.
Article
Neurosciences
Oliver J. Ziff, Jasmine Harley, Yiran Wang, Jacob Neeves, Giulia Tyzack, Fairouz Ibrahim, Mark Skehel, Anob M. Chakrabarti, Gavin Kelly, Rickie Patani
Summary: This study investigates the mislocalization of mRNA and protein in ALS patients. The findings suggest a link between RBP mislocalization and mRNA redistribution in ALS motor neurons. Treatment with the VCP ATPase inhibitor ML240 partially restores mRNA and protein localization and reduces oxidative stress and DNA damage.
Article
Biochemistry & Molecular Biology
Giuseppe Nicastro, Giancarlo Abis, Pierre Klein, Sofia Esteban-Serna, Christopher Gallagher, Belen Chaves-Arquero, Yuyang Cai, Angelo Miguel Figueiredo, Stephen R. Martin, Rickie Patani, Ian A. Taylor, Andres Ramos
Summary: m6A methylation is an important regulatory layer in organismal development and is associated with various cancers and neuro-pathologies. RNA binding proteins, known as m6A readers, integrate the information encoded by m6A methylation into existing RNA regulatory networks. This study reveals that the reader IMP1 recognizes m6A through a specific hydrophobic platform, forming a stable and high-affinity interaction. The recognition is conserved across evolution and independent of the sequence context, but builds upon the strong sequence specificity of IMP1 for GGAC RNA. These findings propose a context-dependent role for methylation in the recognition of IMP1 targets, dependent on the cellular concentration of IMP1, as opposed to the YTH proteins.
NUCLEIC ACIDS RESEARCH
(2023)
Review
Neurosciences
Marija Petrie Howe, Rickie Patani
Summary: The processes of mRNA export and translation play important roles in gene expression regulation in eukaryotic cells, particularly in highly polarised cells like neurons. Nonsense-mediated mRNA decay (NMD) is a translation-dependent quality control process that regulates gene expression in the nervous system and is involved in neurodevelopment, learning, and memory formation. Dysregulation of NMD has been linked to various neurodevelopmental and neurodegenerative disorders. This article discusses the role of NMD and mRNA translation in neuronal functions, with a focus on their involvement in the molecular pathogenesis of neurodegeneration. Additionally, it explores the therapeutic potential and challenges of targeting these processes in neurological diseases that currently lack effective treatments.
TRENDS IN NEUROSCIENCES
(2023)
Meeting Abstract
Cell & Tissue Engineering
Rebecca Powell, Parmjit Jat, Rickie Patani, Kristjan Jessen, James B. Phillips
TISSUE ENGINEERING PART A
(2022)
Review
Clinical Neurology
Phillip Smethurst, Hannah Franklin, Benjamin E. Clarke, Katie Sidle, Rickie Patani
Summary: Accumulating evidence suggests that astrocytes play a key role in neurodegenerative diseases by dealing with pathological protein aggregates and their prion-like behavior. However, their specific functions and their interactions with the disease process are still unclear.