ORCID Profile
0000-0002-9334-8107
Current Organisation
University of Queensland
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Regenerative Medicine (incl. Stem Cells and Tissue Engineering) | Developmental Genetics (incl. Sex Determination) | Medical Biochemistry and Metabolomics | Characterisation of Biological Macromolecules | Medicinal and Biomolecular Chemistry | Regenerative medicine (incl. stem cells) | Genetics | Biologically Active Molecules | Central Nervous System | Gene expression (incl. microarray and other genome-wide approaches) | Epigenetics (incl. genome methylation and epigenomics) | Proteins and Peptides | Genetics | Medical Biochemistry and Metabolomics not elsewhere classified | Nanobiotechnology
ANZSRC Socio-Economic Objective (SEO)
Cardiovascular System and Diseases | Nervous System and Disorders | Expanding Knowledge in the Biological Sciences | Expanding Knowledge in the Agricultural and Veterinary Sciences | Blood Disorders |
Related Links
Publications
Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts
Publisher: Springer Science and Business Media LLC
Date: 05-08-2012
DOI: 10.1038/NATURE11317
ALPK2 Promotes Cardiogenesis in Zebrafish and Human Pluripotent Stem Cells
Publisher: Elsevier BV
Date: 04-2018
Subtle modifications to oxytocin produce ligands that retain potency and improved selectivity across species.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 05-12-2017
DOI: 10.1126/SCISIGNAL.AAN3398
Abstract: An oxytocin derivative that may not trigger adverse side effects has been generated.
Defining the Fetal Gene Program at Single-Cell Resolution in Pediatric Dilated Cardiomyopathy
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-10-2022
Single-cell RNA-seq of human induced pluripotent stem cells reveals cellular heterogeneity and cell state transitions between subpopulations
Publisher: Cold Spring Harbor Laboratory
Date: 11-05-2018
Abstract: Heterogeneity of cell states represented in pluripotent cultures has not been described at the transcriptional level. Since gene expression is highly heterogeneous between cells, single-cell RNA sequencing can be used to identify how in idual pluripotent cells function. Here, we present results from the analysis of single-cell RNA sequencing data from 18,787 in idual WTC-CRISPRi human induced pluripotent stem cells. We developed an unsupervised clustering method and, through this, identified four subpopulations distinguishable on the basis of their pluripotent state, including a core pluripotent population (48.3%), proliferative (47.8%), early primed for differentiation (2.8%), and late primed for differentiation (1.1%). For each subpopulation, we were able to identify the genes and pathways that define differences in pluripotent cell states. Our method identified four transcriptionally distinct predictor gene sets composed of 165 unique genes that denote the specific pluripotency states using these sets, we developed a multigenic machine learning prediction method to accurately classify single cells into each of the subpopulations. Compared against a set of established pluripotency markers, our method increases prediction accuracy by 10%, specificity by 20%, and explains a substantially larger proportion of deviance (up to threefold) from the prediction model. Finally, we developed an innovative method to predict cells transitioning between subpopulations and support our conclusions with results from two orthogonal pseudotime trajectory methods.
Don’t Turn Off the Tap! The Importance of Discovery Science to the Australian Cardiovascular Sector and Improving Clinical Outcomes Into the Future
Publisher: Elsevier BV
Date: 10-2022
DOI: 10.1016/J.HLC.2022.06.669
Abstract: Despite significant advances in interventional and therapeutic approaches, cardiovascular disease (CVD) remains the leading cause of death and mortality. To lower this health burden, cardiovascular discovery scientists need to play an integral part in the solution. Successful clinical translation is achieved when built upon a strong foundational understanding of the disease mechanisms involved. Changes in the Australian funding landscape, to place greater emphasis on translation, however, have increased job insecurity for discovery science researchers and especially early-mid career researchers. To highlight the importance of discovery science in cardiovascular research, this review compiles six science stories in which fundamental discoveries, often involving Australian researchers, has led to or is advancing to clinical translation. These stories demonstrate the importance of the role of discovery scientists and the need for their work to be prioritised now and in the future. Australia needs to keep discovery scientists supported and fully engaged within the broader cardiovascular research ecosystem so they can help realise the next game-changing therapy or diagnostic approach that diminishes the burden of CVD on society.
Cardiopoietry in Motion
Publisher: Elsevier BV
Date: 06-2013
New Drug Targets and Preclinical Modelling Recommendations for Treating Acute Myocardial Infarction
Publisher: Elsevier BV
Date: 07-2023
Inferring cell diversity in single cell data using consortium-scale epigenetic data as a biological anchor for cell identity
Publisher: Oxford University Press (OUP)
Date: 05-2023
DOI: 10.1093/NAR/GKAD307
Abstract: Methods for cell clustering and gene expression from single-cell RNA sequencing (scRNA-seq) data are essential for biological interpretation of cell processes. Here, we present TRIAGE-Cluster which uses genome-wide epigenetic data from erse bio-s les to identify genes demarcating cell ersity in scRNA-seq data. By integrating patterns of repressive chromatin deposited across erse cell types with weighted density estimation, TRIAGE-Cluster determines cell type clusters in a 2D UMAP space. We then present TRIAGE-ParseR, a machine learning method which evaluates gene expression rank lists to define gene groups governing the identity and function of cell types. We demonstrate the utility of this two-step approach using atlases of in vivo and in vitro cell ersification and organogenesis. We also provide a web accessible dashboard for analysis and download of data and software. Collectively, genome-wide epigenetic repression provides a versatile strategy to define cell ersity and study gene regulation of scRNA-seq data.
Temporal perturbation of histone deacetylase activity reveals a requirement for HDAC1–3 in mesendoderm cell differentiation
Publisher: Elsevier BV
Date: 05-2022
DOI: 10.1016/J.CELREP.2022.110818
Abstract: Histone deacetylases (HDACs) are a class of enzymes that control chromatin state and influence cell fate. We evaluated the chromatin accessibility and transcriptome dynamics of zinc-containing HDACs during cell differentiation in vitro coupled with chemical perturbation to identify the role of HDACs in mesendoderm cell fate specification. Single-cell RNA sequencing analyses of HDAC expression during human pluripotent stem cell (hPSC) differentiation in vitro and mouse gastrulation in vivo reveal a unique association of HDAC1 and -3 with mesendoderm gene programs during exit from pluripotency. Functional perturbation with small molecules reveals that inhibition of HDAC1 and -3, but not HDAC2, induces mesoderm while impeding endoderm and early cardiac progenitor specification. These data identify unique biological functions of the structurally homologous enzymes HDAC1-3 in influencing hPSC differentiation from pluripotency toward mesendodermal and cardiac progenitor populations.
Evidence for Minimal Cardiogenic Potential of Stem Cell Antigen 1–Positive Cells in the Adult Mouse Heart
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-12-2018
Organization of gene programs revealed by unsupervised analysis of diverse gene-trait associations
Publisher: Oxford University Press (OUP)
Date: 18-06-2022
DOI: 10.1093/NAR/GKAC413
Abstract: Genome wide association studies provide statistical measures of gene–trait associations that reveal how genetic variation influences phenotypes. This study develops an unsupervised dimensionality reduction method called UnTANGLeD (Unsupervised Trait Analysis of Networks from Gene Level Data) which organizes 16,849 genes into discrete gene programs by measuring the statistical association between genetic variants and 1,393 erse complex traits. UnTANGLeD reveals 173 gene clusters enriched for protein–protein interactions and highly distinct biological processes governing development, signalling, disease, and homeostasis. We identify erse gene networks with robust interactions but not associated with known biological processes. Analysis of independent disease traits shows that UnTANGLeD gene clusters are conserved across all complex traits, providing a simple and powerful framework to predict novel gene candidates and programs influencing orthogonal disease phenotypes. Collectively, this study demonstrates that gene programs co-ordinately orchestrating cell functions can be identified without reliance on prior knowledge, providing a method for use in functional annotation, hypothesis generation, machine learning and prediction algorithms, and the interpretation of erse genomic data.
Aesthetic Cardiology: Adipose-Derived Stem Cells for Myocardial Repair
Publisher: Bentham Science Publishers Ltd.
Date: 06-2010
Single histidine-substituted cardiac troponin I confers protection from age-related systolic and diastolic dysfunction
Publisher: Oxford University Press (OUP)
Date: 16-07-2008
DOI: 10.1093/CVR/CVN198
A village in a dish model system for population-scale hiPSC studies
Publisher: Springer Science and Business Media LLC
Date: 09-06-2023
DOI: 10.1038/S41467-023-38704-1
Abstract: The mechanisms by which DNA alleles contribute to disease risk, drug response, and other human phenotypes are highly context-specific, varying across cell types and different conditions. Human induced pluripotent stem cells are uniquely suited to study these context-dependent effects but cell lines from hundreds or thousands of in iduals are required. Village cultures, where multiple induced pluripotent stem lines are cultured and differentiated in a single dish, provide an elegant solution for scaling induced pluripotent stem experiments to the necessary s le sizes required for population-scale studies. Here, we show the utility of village models, demonstrating how cells can be assigned to an induced pluripotent stem line using single-cell sequencing and illustrating that the genetic, epigenetic or induced pluripotent stem line-specific effects explain a large percentage of gene expression variation for many genes. We demonstrate that village methods can effectively detect induced pluripotent stem line-specific effects, including sensitive dynamics of cell states.
Inhibition of β-catenin signaling respecifies anterior-like endothelium into beating human cardiomyocytes
Publisher: The Company of Biologists
Date: 2015
DOI: 10.1242/DEV.117010
Abstract: During vertebrate development, mesodermal fate choices are regulated by interactions between morphogens such as activin/nodal, BMPs and Wnt/β-catenin that define anterior-posterior patterning and specify downstream derivatives including cardiomyocyte, endothelial and hematopoietic cells. We used human embryonic stem cells to explore how these pathways control mesodermal fate choices in vitro. Varying doses of activin A and BMP4 to mimic cytokine gradient polarization in the anterior-posterior axis of the embryo led to differential activity of Wnt/β-catenin signaling and specified distinct anterior-like (high activin/low BMP) and posterior-like (low activin/high BMP) mesodermal populations. Cardiogenic mesoderm was generated under conditions specifying anterior-like mesoderm, whereas blood-forming endothelium was generated from posterior-like mesoderm, and vessel-forming CD31+ endothelial cells were generated from all mesoderm origins. Surprisingly, inhibition of β-catenin signaling led to the highly efficient respecification of anterior-like endothelium into beating cardiomyocytes. Cardiac respecification was not observed in posterior-derived endothelial cells. Thus, activin/BMP gradients specify distinct mesodermal subpopulations that generate cell derivatives with unique angiogenic, hemogenic and cardiogenic properties that should be useful for understanding embryogenesis and developing therapeutics.
Genotype-free demultiplexing of pooled single-cell RNA-seq
Publisher: Springer Science and Business Media LLC
Date: 12-2019
DOI: 10.1186/S13059-019-1852-7
Abstract: A variety of methods have been developed to demultiplex pooled s les in a single cell RNA sequencing (scRNA-seq) experiment which either require hashtag barcodes or s le genotypes prior to pooling. We introduce scSplit which utilizes genetic differences inferred from scRNA-seq data alone to demultiplex pooled s les. scSplit also enables mapping clusters to original s les. Using simulated, merged, and pooled multi-in idual datasets, we show that scSplit prediction is highly concordant with demuxlet predictions and is highly consistent with the known truth in cell-hashing dataset. scSplit is ideally suited to s les without external genotype information and is available at: on-xu/scSplit
Dynamic chromatin organization and regulatory interactions in human endothelial cell differentiation
Publisher: Cold Spring Harbor Laboratory
Date: 16-04-2022
DOI: 10.1101/2022.04.15.488491
Abstract: Vascular endothelial cells are a mesoderm-derived lineage with many essential functions, including angiogenesis and coagulation. However, the gene regulatory mechanisms that underpin endothelial specialization are largely unknown, as are the roles of 3D chromatin organization in regulating endothelial cell transcription. To investigate the relationships between 3D chromatin organization and gene expression in endothelial cell differentiation, we induced endothelial cell differentiation from human pluripotent stem cells and performed Hi-C and RNA-seq assays at specific timepoints in differentiation. Our analyses reveal that long-range intrachromosomal contacts increase over the course of endothelial cell differentiation, as do genomic compartment transitions between active and inactive states. These compartmental states are tightly associated with endothelial transcription. Dynamic topologically associating domain (TAD) boundaries strengthen and converge on an endothelial cell state, and nascent TAD boundaries are linked to the expression of genes that support endothelial cell specification. Relatedly, chromatin pairwise point interactions (DNA loops) increase in frequency during differentiation and are linked to the expression of genes with essential roles in vascular biology, including MECOM, TFPI , and KDR . To identify forms of regulation specific to endothelial cell differentiation, we compared the functional chromatin dynamics of endothelial cells with those of developing cardiomyocytes. Cardiomyocytes exhibit greater long-range cis interactions than endothelial cells, whereas endothelial cells have increased local intra-TAD interactions and much more abundant pairwise point interactions. Genome topology changes dynamically during endothelial differentiation, including acquisition of long-range cis interactions and new TAD boundaries, interconversion of hetero- and euchromatin, and formation of DNA loops. These chromatin dynamics guide transcription in the development of endothelial cells and promote the ergence of endothelial cells from related cell types such as cardiomyocytes.
Genotype-free demultiplexing of pooled single-cell RNA-seq
Publisher: Cold Spring Harbor Laboratory
Date: 07-03-2019
DOI: 10.1101/570614
Abstract: A variety of experimental and computational methods have been developed to demultiplex s les from pooled in iduals in a single-cell RNA sequencing (scRNA-Seq) experiment which either require adding information (such as hashtag barcodes) or measuring information (such as genotypes) prior to pooling. We introduce scSplit which utilises genetic differences inferred from scRNA-Seq data alone to demultiplex pooled s les. scSplit also extracts a minimal set of high confidence presence/absence genotypes in each cluster which can be used to map clusters to original s les. Using a range of simulated, merged in idual-s le as well as pooled multi-in idual scRNA-Seq datasets, we show that scSplit is highly accurate and concordant with demuxlet predictions. Furthermore, scSplit predictions are highly consistent with the known truth in cell-hashing dataset. We also show that multiplexed-scRNA-Seq can be used to reduce batch effects caused by technical biases. scSplit is ideally suited to s les for which external genome-wide genotype data cannot be obtained (for ex le non-model organisms), or for which it is impossible to obtain unmixed s les directly, such as mixtures of genetically distinct tumour cells, or mixed infections. scSplit is available at: on-xu/scSplit
Reprogramming the injured heart
Publisher: Springer Science and Business Media LLC
Date: 05-2012
DOI: 10.1038/485585A
A critical examination of qur'an 4:34 and its relevance to intimate partner violence in muslim families
Publisher: Informa UK Limited
Date: 30-12-2010
Diastolic dysfunction and thin filament dysregulation resulting from excitation–contraction uncoupling in a mouse model of restrictive cardiomyopathy
Publisher: Elsevier BV
Date: 09-2012
Proliferation at the Heart of Preadolescence
Publisher: Elsevier BV
Date: 05-2014
DOI: 10.1016/J.CELL.2014.04.025
Abstract: Cardiomyocytes, the cells of the heart muscle, lose nearly all of their proliferative capacity after birth, limiting the heart's ability to regenerate. Naqvi et al. now identify a transient burst of cardiomyocyte proliferation during preadolescence, driven by a thyroid hormone surge, with therapeutic implications for congenital and acquired heart diseases.
Influence of genetic background on ex vivo and in vivo cardiac function in several commonly used inbred mouse strains
Publisher: American Physiological Society
Date: 10-2010
DOI: 10.1152/PHYSIOLGENOMICS.00071.2010
Abstract: Inbred mouse strains play a critical role in biomedical research. Genetic homogeneity within inbred strains and their general amenability to genetic manipulation have made them an ideal resource for dissecting the physiological function(s) of in idual genes. However, the inbreeding that makes inbred mice so useful also results in genetic ergence between them. This genetic ergence is often unaccounted for but may be a confounding factor when comparing studies that have utilized distinct inbred strains. Here, we compared the cardiac function of C57BL/6J mice to seven other commonly used inbred mouse strains: FVB/NJ, DBA/2J, C3H/HeJ, BALB/cJ, 129X1/SvJ, C57BL/10SnJ, and 129S1/SvImJ. The assays used to compare cardiac function were the ex vivo isolated Langendorff heart preparation and in vivo real-time hemodynamic analysis using conductance micromanometry. We report significant strain-dependent differences in cardiac function between C57BL/6J and other commonly used inbred strains. C57BL/6J maintained better cardiac function than most inbred strains after ex vivo ischemia, particularly compared with 129S1/SvImJ, 129X1/SvJ, and C57BL/10SnJ strains. However, during in vivo acute hypoxia 129X1/SvJ and 129S1/SvImJ maintained relatively normal cardiac function, whereas C57BL/6J animals showed dramatic cardiac decompensation. Additionally, C3H/HeJ showed rapid and marked cardiac decompensation in response to esmolol infusion compared with effects of other strains. These findings demonstrate the complex effects of genetic ergence between inbred strains on cardiac function. These results may help inform analysis of gene ablation or transgenic studies and further demonstrate specific quantitative traits that could be useful in discovery of genetic modifiers relevant to cardiac health and disease.
A transposable element into the human long noncoding RNA CARMEN is a switch for cardiac precursor cell specification
Publisher: Oxford University Press (OUP)
Date: 20-12-2022
DOI: 10.1093/CVR/CVAC191
Abstract: The major cardiac cell types composing the adult heart arise from common multipotent precursor cells. Cardiac lineage decisions are guided by extrinsic and cell-autonomous factors, including recently discovered long noncoding RNAs (lncRNAs). The human lncRNA CARMEN, which is known to dictate specification toward the cardiomyocyte (CM) and the smooth muscle cell (SMC) fates, generates a ersity of alternatively spliced isoforms. The CARMEN locus can be manipulated to direct human primary cardiac precursor cells (CPCs) into specific cardiovascular fates. Investigating CARMEN isoform usage in differentiating CPCs represents therefore a unique opportunity to uncover isoform-specific functions in lncRNAs. Here, we identify one CARMEN isoform, CARMEN-201, to be crucial for SMC commitment. CARMEN-201 activity is encoded within an alternatively spliced exon containing a MIRc short interspersed nuclear element. This element binds the transcriptional repressor REST (RE1 Silencing Transcription Factor), targets it to cardiogenic loci, including ISL1, IRX1, IRX5, and SFRP1, and thereby blocks the CM gene program. In turn, genes regulating SMC differentiation are induced. These data show how a critical physiological switch is wired by alternative splicing and functional transposable elements in a long noncoding RNA. They further demonstrated the crucial importance of the lncRNA isoform CARMEN-201 in SMC specification during heart development.
Pathogenic peptide deviations support a model of adaptive evolution of chordate cardiac performance by troponin mutations
Publisher: American Physiological Society
Date: 07-2010
DOI: 10.1152/PHYSIOLGENOMICS.00033.2010
Abstract: In cardiac muscle, the troponin (cTn) complex is a key regulator of myofilament calcium sensitivity because it serves as a molecular switch required for translating myocyte calcium fluxes into sarcomeric contraction and relaxation. Studies of several species suggest that ectotherm chordates have myofilaments with heightened calcium responsiveness. However, genetic polymorphisms in cTn that cause increased myofilament sensitivity to activating calcium in mammals result in cardiac disease including arrhythmias, diastolic dysfunction, and increased susceptibility to sudden cardiac death. We hypothesized that specific residue modifications in the regulatory arm of troponin I (TnI) were critical in mediating the observed decrease in myofilament calcium sensitivity within the mammalian taxa. We performed large-scale phylogenetic analysis, atomic resolution molecular dynamics simulations and modeling, and computational alanine scanning. This study provides evidence that a His to Ala substitution within mammalian cardiac TnI (cTnI) reduced the thermodynamic potential at the interface between cTnI and cardiac TnC (cTnC) in the calcium-saturated state by disrupting a strong intermolecular electrostatic interaction. This key residue modification reduced myofilament calcium sensitivity by making cTnI molecularly untethered from cTnC. To meet the requirements for refined mammalian adult cardiac performance, we propose that compensatory evolutionary pressures favored mutations that enhanced the relaxation properties of cTn by decreasing its sensitivity to activating calcium.
Statistically based splicing detection reveals neural enrichment and tissue-specific induction of circular RNA during human fetal development
Publisher: Springer Science and Business Media LLC
Date: 16-06-2015
Cardiac Development in Zebrafish and Human Embryonic Stem Cells Is Inhibited by Exposure to Tobacco Cigarettes and E-Cigarettes
Publisher: Public Library of Science (PLoS)
Date: 15-05-2015
Single cell eQTL analysis identifies cell type-specific genetic control of gene expression in fibroblasts and reprogrammed induced pluripotent stem cells
Publisher: Springer Science and Business Media LLC
Date: 05-03-2021
DOI: 10.1186/S13059-021-02293-3
Abstract: The discovery that somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs) has provided a foundation for in vitro human disease modelling, drug development and population genetics studies. Gene expression plays a critical role in complex disease risk and therapeutic response. However, while the genetic background of reprogrammed cell lines has been shown to strongly influence gene expression, the effect has not been evaluated at the level of in idual cells which would provide significant resolution. By integrating single cell RNA-sequencing (scRNA-seq) and population genetics, we apply a framework in which to evaluate cell type-specific effects of genetic variation on gene expression. Here, we perform scRNA-seq on 64,018 fibroblasts from 79 donors and map expression quantitative trait loci (eQTLs) at the level of in idual cell types. We demonstrate that the majority of eQTLs detected in fibroblasts are specific to an in idual cell subtype. To address if the allelic effects on gene expression are maintained following cell reprogramming, we generate scRNA-seq data in 19,967 iPSCs from 31 reprogramed donor lines. We again identify highly cell type-specific eQTLs in iPSCs and show that the eQTLs in fibroblasts almost entirely disappear during reprogramming. This work provides an atlas of how genetic variation influences gene expression across cell subtypes and provides evidence for patterns of genetic architecture that lead to cell type-specific eQTL effects.
Therapeutic Inhibition of Acid-Sensing Ion Channel 1a Recovers Heart Function After Ischemia-Reperfusion Injury.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 21-09-2021
DOI: 10.1161/CIRCULATIONAHA.121.054360
Abstract: Ischemia–reperfusion injury (IRI) is one of the major risk factors implicated in morbidity and mortality associated with cardiovascular disease. During cardiac ischemia, the buildup of acidic metabolites results in decreased intracellular and extracellular pH, which can reach as low as 6.0 to 6.5. The resulting tissue acidosis exacerbates ischemic injury and significantly affects cardiac function. We used genetic and pharmacologic methods to investigate the role of acid-sensing ion channel 1a (ASIC1a) in cardiac IRI at the cellular and whole-organ level. Human induced pluripotent stem cell–derived cardiomyocytes as well as ex vivo and in vivo models of IRI were used to test the efficacy of ASIC1a inhibitors as pre- and postconditioning therapeutic agents. Analysis of human complex trait genetics indicates that variants in the ASIC1 genetic locus are significantly associated with cardiac and cerebrovascular ischemic injuries. Using human induced pluripotent stem cell–derived cardiomyocytes in vitro and murine ex vivo heart models, we demonstrate that genetic ablation of ASIC1a improves cardiomyocyte viability after acute IRI. Therapeutic blockade of ASIC1a using specific and potent pharmacologic inhibitors recapitulates this cardioprotective effect. We used an in vivo model of myocardial infarction and 2 models of ex vivo donor heart procurement and storage as clinical models to show that ASIC1a inhibition improves post-IRI cardiac viability. Use of ASIC1a inhibitors as preconditioning or postconditioning agents provided equivalent cardioprotection to benchmark drugs, including the sodium-hydrogen exchange inhibitor zoniporide. At the cellular and whole organ level, we show that acute exposure to ASIC1a inhibitors has no effect on cardiac ion channels regulating baseline electromechanical coupling and physiologic performance. Our data provide compelling evidence for a novel pharmacologic strategy involving ASIC1a blockade as a cardioprotective therapy to improve the viability of hearts subjected to IRI.
Methods for Assessing the Electromechanical Integration of Human Pluripotent Stem Cell-Derived Cardiomyocyte Grafts
Publisher: Springer New York
Date: 2014
Chromatin and Transcriptional Analysis of Mesoderm Progenitor Cells Identifies HOPX as a Regulator of Primitive Hematopoiesis
Publisher: Elsevier BV
Date: 08-2017
Cardiac disease in mucopolysaccharidosis type I attributed to catecholaminergic and hemodynamic deficiencies
Publisher: American Physiological Society
Date: 2011
DOI: 10.1152/AJPHEART.00774.2010
Abstract: Cardiac dysfunction is a common cause of death among pediatric patients with mutations in the lysosomal hydrolase α-l-iduronidase ( IDUA) gene, which causes mucopolysaccharidosis type I (MPS-I). The purpose of this study was to analyze adrenergic regulation of cardiac hemodynamic function in MPS-I. An analysis of murine heart function was performed using conductance micromanometry to assess in vivo cardiac hemodynamics. Although MPS-I ( IDUA −/− ) mice were able to maintain normal cardiac output and ejection fraction at baseline, this cohort had significantly compromised systolic and diastolic function compared with IDUA +/− control mice. During dobutamine infusion MPS-I mice did not significantly increase cardiac output from baseline, indicative of blunted cardiac reserve. Autonomic tone, measured functionally by β-blockade, indicated that MPS-I mice required catecholaminergic stimulation to maintain baseline hemodynamics. Survival analysis showed mortality only among MPS-I mice. Linear regression analysis revealed that heightened end-systolic volume in the resting heart is significantly correlated with susceptibility to mortality in MPS-I hearts. This study reveals that cardiac remodeling in the pathology of MPS-I involves heightened adrenergic tone at the expense of cardiac reserve with cardiac decompensation predicted on the basis of increased baseline systolic volumes.
Non-canonical Wnt signaling enhances differentiation of Sca1+/c-kit+ adipose-derived murine stromal vascular cells into spontaneously beating cardiac myocytes
Publisher: Elsevier BV
Date: 09-2007
Elp2 mutations perturb the epitranscriptome and lead to a complex neurodevelopmental phenotype.
Publisher: Springer Science and Business Media LLC
Date: 11-05-2021
DOI: 10.1038/S41467-021-22888-5
Abstract: Intellectual disability (ID) and autism spectrum disorder (ASD) are the most common neurodevelopmental disorders and are characterized by substantial impairment in intellectual and adaptive functioning, with their genetic and molecular basis remaining largely unknown. Here, we identify biallelic variants in the gene encoding one of the Elongator complex subunits, ELP2, in patients with ID and ASD. Modelling the variants in mice recapitulates the patient features, with brain imaging and tractography analysis revealing microcephaly, loss of white matter tract integrity and an aberrant functional connectome. We show that the Elp2 mutations negatively impact the activity of the complex and its function in translation via tRNA modification. Further, we elucidate that the mutations perturb protein homeostasis leading to impaired neurogenesis, myelin loss and neurodegeneration. Collectively, our data demonstrate an unexpected role for tRNA modification in the pathogenesis of monogenic ID and ASD and define Elp2 as a key regulator of brain development.
Integrating single-cell genomics pipelines to discover mechanisms of stem cell differentiation
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1016/J.MOLMED.2021.09.006
Abstract: Pluripotent stem cells underpin a growing sector that leverages their differentiation potential for research, industry, and clinical applications. This review evaluates the landscape of methods in single-cell transcriptomics that are enabling accelerated discovery in stem cell science. We focus on strategies for scaling stem cell differentiation through multiplexed single-cell analyses, for evaluating molecular regulation of cell differentiation using new analysis algorithms, and methods for integration and projection analysis to classify and benchmark stem cell derivatives against in vivo cell types. By discussing the available methods, comparing their strengths, and illustrating strategies for developing integrated analysis pipelines, we provide user considerations to inform their implementation and interpretation.
Cavin4 interacts with Bin1 to promote T-tubule formation and stability in developing skeletal muscle
Publisher: Rockefeller University Press
Date: 11-10-2021
Abstract: The cavin proteins are essential for caveola biogenesis and function. Here, we identify a role for the muscle-specific component, Cavin4, in skeletal muscle T-tubule development by analyzing two vertebrate systems, mouse and zebrafish. In both models, Cavin4 localized to T-tubules, and loss of Cavin4 resulted in aberrant T-tubule maturation. In zebrafish, which possess duplicated cavin4 paralogs, Cavin4b was shown to directly interact with the T-tubule–associated BAR domain protein Bin1. Loss of both Cavin4a and Cavin4b caused aberrant accumulation of interconnected caveolae within the T-tubules, a fragmented T-tubule network enriched in Caveolin-3, and an impaired Ca2+ response upon mechanical stimulation. We propose a role for Cavin4 in remodeling the T-tubule membrane early in development by recycling caveolar components from the T-tubule to the sarcolemma. This generates a stable T-tubule domain lacking caveolae that is essential for T-tubule function.
Single histidine button in cardiac troponin I sustains heart performance in response to severe hypercapnic respiratory acidosis in vivo
Publisher: Wiley
Date: 13-01-2009
DOI: 10.1096/FJ.08-121996
Zinc finger nucleases: looking toward translation
Publisher: Springer Science and Business Media LLC
Date: 09-02-2012
DOI: 10.1038/GT.2012.2
Abstract: Genetic engineering has emerged as a powerful mechanism for understanding biological systems and a potential approach for redressing congenital disease. Alongside, the emergence of these technologies in recent decades has risen the complementary analysis of the ethical implications of genetic engineering techniques and applications. Although viral-mediated approaches have dominated initial efforts in gene transfer (GT) methods, an emerging technology involving engineered restriction enzymes known as zinc finger nucleases (ZFNs) has become a powerful new methodology for gene editing. Given the advantages provided by ZFNs for more specific and erse approaches in gene editing for basic science and clinical applications, we discuss how ZFN research can address some of the ethical and scientific questions that have been posed for other GT techniques. This is of particular importance, given the momentum currently behind ZFNs in moving into phase I clinical trials. This study provides a historical account of the origins of ZFN technology, an analysis of current techniques and applications, and an examination of the ethical issues applicable to translational ZFN genetic engineering in early phase clinical trials.
Nkx2.5 marks angioblasts that contribute to hemogenic endothelium of the endocardium and dorsal aorta
Publisher: eLife Sciences Publications, Ltd
Date: 08-03-2017
DOI: 10.7554/ELIFE.20994
Abstract: Novel regenerative therapies may stem from deeper understanding of the mechanisms governing cardiovascular lineage ersification. Using enhancer mapping and live imaging in avian embryos, and genetic lineage tracing in mice, we investigated the spatio-temporal dynamics of cardiovascular progenitor populations. We show that expression of the cardiac transcription factor Nkx2.5 marks a mesodermal population outside of the cardiac crescent in the extraembryonic and lateral plate mesoderm, with characteristics of hemogenic angioblasts. Extra-cardiac Nkx2.5 lineage progenitors migrate into the embryo and contribute to clusters of CD41+/CD45+ and RUNX1+ cells in the endocardium, the aorta-gonad-mesonephros region of the dorsal aorta and liver. We also demonstrated that ectopic expression of Nkx2.5 in chick embryos activates the hemoangiogenic gene expression program. Taken together, we identified a hemogenic angioblast cell lineage characterized by transient Nkx2.5 expression that contributes to hemogenic endothelium and endocardium, suggesting a novel role for Nkx2.5 in hemoangiogenic lineage specification and ersification.
Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts
Publisher: Springer Science and Business Media LLC
Date: 30-04-2014
DOI: 10.1038/NATURE13233
Genetic Lineage Tracing of Sca-1 + Cells Reveals Endothelial but Not Myogenic Contribution to the Murine Heart
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-12-2018
DOI: 10.1161/CIRCULATIONAHA.118.035210
Abstract: The adult mammalian heart displays a cardiomyocyte turnover rate of ≈1%/y throughout postnatal life and after injuries such as myocardial infarction (MI), but the question of which cell types drive this low level of new cardiomyocyte formation remains contentious. Cardiac-resident stem cells marked by stem cell antigen-1 (Sca-1, gene name Ly6a ) have been proposed as an important source of cardiomyocyte renewal. However, the in vivo contribution of endogenous Sca-1 + cells to the heart at baseline or after MI has not been investigated. Here we generated Ly6a gene–targeted mice containing either a constitutive or an inducible Cre recombinase to perform genetic lineage tracing of Sca-1 + cells in vivo. We observed that the contribution of endogenous Sca-1 + cells to the cardiomyocyte population in the heart was .005% throughout all of cardiac development, with aging, or after MI. In contrast, Sca-1 + cells abundantly contributed to the cardiac vasculature in mice during physiological growth and in the post-MI heart during cardiac remodeling. Specifically, Sca-1 lineage-traced endothelial cells expanded postnatally in the mouse heart after birth and into adulthood. Moreover, pulse labeling of Sca-1 + cells with an inducible Ly6a -MerCreMer allele also revealed a preferential expansion of Sca-1 lineage-traced endothelial cells after MI injury in the mouse. Cardiac-resident Sca-1 + cells are not significant contributors to cardiomyocyte renewal in vivo. However, cardiac Sca-1 + cells represent a subset of vascular endothelial cells that expand postnatally with enhanced responsiveness to pathological stress in vivo.
Molecular Cardiology in Translation: Gene, Cell and Chemical-Based Experimental Therapeutics for the Failing Heart
Publisher: Springer Science and Business Media LLC
Date: 10-2008
Combined Mesenchymal Stromal Cell Therapy and Extracorporeal Membrane Oxygenation in Acute Respiratory Distress Syndrome. A Randomized Controlled Trial in Sheep
Publisher: American Thoracic Society
Date: 08-2020
An integrated cell barcoding and computational analysis pipeline for scalable analysis of differentiation at single-cell resolution
Publisher: Cold Spring Harbor Laboratory
Date: 14-10-2022
DOI: 10.1101/2022.10.12.511862
Abstract: This study develops a versatile cell multiplexing and data analysis platform to gain knowledge gain into mechanisms of cell differentiation. We engineer a cell barcoding system in human cells enabling multiplexed single-cell RNA sequencing for high throughput perturbation of customisable and erse experimental conditions. This is coupled with a new computational analysis pipeline that overcomes the limitations of conventional algorithms by using an unsupervised, genome-wide, orthogonal biological reference point to reveal the cell ersity and regulatory networks in the input scRNA-seq data set. We implement this pipeline by engineering transcribed barcodes into induced pluripotent stem cells and multiplex 62 independent experimental conditions comprising eight differentiation time points and nine developmental signalling perturbations in duplicates. We identify and deconstruct the temporal, signalling, and gene regulatory imperatives of iPSC differentiation into cell types of ectoderm, mesoderm, and endoderm lineages. This study provides a cellular and computational pipeline to study cell differentiation applicable to studies in developmental biology, drug discovery, and disease modelling.
Artificial Selection for Whole Animal Low Intrinsic Aerobic Capacity Co-Segregates with Hypoxia-Induced Cardiac Pump Failure
Publisher: Public Library of Science (PLoS)
Date: 07-2009
Generating high-purity cardiac and endothelial derivatives from patterned mesoderm using human pluripotent stem cells
Publisher: Springer Science and Business Media LLC
Date: 12-2016
The developmental origins and lineage contributions of endocardial endothelium
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1016/J.BBAMCR.2016.01.022
Abstract: Endocardial development involves a complex orchestration of cell fate decisions that coordinate with endoderm formation and other mesodermal cell lineages. Historically, investigations into the contribution of endocardium in the developing embryo was constrained to the heart where these cells give rise to the inner lining of the myocardium and are a major contributor to valve formation. In recent years, studies have continued to elucidate the complexities of endocardial fate commitment revealing a much broader scope of lineage potential from developing endocardium. These studies cover a wide range of species and model systems and show direct contribution or fate potential of endocardium giving rise to cardiac vasculature, blood, fibroblast, and cardiomyocyte lineages. This review focuses on the marked expansion of knowledge in the area of endocardial fate potential. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.
A transcribed enhancer dictates mesendoderm specification in pluripotency
Publisher: Springer Science and Business Media LLC
Date: 27-11-2017
DOI: 10.1038/S41467-017-01804-W
Abstract: Enhancers and long noncoding RNAs (lncRNAs) are key determinants of lineage specification during development. Here, we evaluate remodeling of the enhancer landscape and modulation of the lncRNA transcriptome during mesendoderm specification. We sort mesendodermal progenitors from differentiating embryonic stem cells (ESCs) according to Eomes expression, and find that enhancer usage is coordinated with mesendoderm-specific expression of key lineage-determining transcription factors. Many of these enhancers are associated with the expression of lncRNAs. Examination of ESC-specific enhancers interacting in three-dimensional space with mesendoderm-specifying transcription factor loci identifies MesEndoderm Transcriptional Enhancer Organizing Region ( Meteor ). Genetic and epigenetic manipulation of the Meteor enhancer reveal its indispensable role during mesendoderm specification and subsequent cardiogenic differentiation via transcription-independent and -dependent mechanisms. Interestingly, Meteor -deleted ESCs are epigenetically redirected towards neuroectodermal lineages. Loci, topologically associating a transcribed enhancer and its cognate protein coding gene, appear to represent therefore a class of genomic elements controlling developmental competence in pluripotency.
Conserved Epigenetic Regulatory Logic Infers Genes Governing Cell Identity
Publisher: Elsevier BV
Date: 12-2020
Human hearts have an intrinsic regenerative potential following myocardial infarction
Publisher: Research Square Platform LLC
Date: 07-09-2023
Targeted Genomic Integration of a Selectable Floxed Dual Fluorescence Reporter in Human Embryonic Stem Cells
Publisher: Public Library of Science (PLoS)
Date: 10-10-2012
Inferring cell diversity in single cell data using consortium-scale epigenetic data as a biological anchor for cell identity
Publisher: Cold Spring Harbor Laboratory
Date: 17-10-2022
DOI: 10.1101/2022.10.12.512003
Abstract: Methods for cell clustering and gene expression from single-cell RNA sequencing (scRNA-seq) data are essential for biological interpretation of cell processes. Here we present TRIAGE-Cluster which uses genome-wide epigenetic data from erse bio-s les to identify genes demarcating cell ersity in scRNA-seq data. TRIAGE-Cluster integrates patterns of repressive chromatin deposited across erse cell types with weighted density estimation to determine cell type clusters in a 2D UMAP space. We then present TRIAGE-ParseR, a machine learning method that evaluates gene expression rank lists to define gene groups governing the identity and function of cell types. We demonstrate the utility of this two-step approach using atlases of in vivo and in vitro cell ersification and organogenesis. We also provide a web accessible dashboard for analysis and download of data and software. Collectively, genome-wide epigenetic repression provides a versatile strategy to define cell ersity and study gene regulation of scRNA-seq data.
pH-Responsive Titratable Inotropic Performance of Histidine-Modified Cardiac Troponin I
Publisher: Elsevier BV
Date: 04-2012
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