Human ISL1+ Ventricular Progenitors Self-Assemble into an In Vivo Functional Heart Patch and Preserve Cardiac Function Post Infarction

Foo, Kylie S.; Lehtinen, Markku; Leung, Chuen Yan; Lian, Xiaojun; Xu, Jiejia; Keung, Wendy; Geng, Lin; Kolstad, Terje R Selnes; Thams, Sebastian; Wong, Andy O.-T.; Wong, Nicodemus; Bylund, Kristine; Zhou, Chikai; He, Xianli; Jin, Shaobo; Clarke, Jonathan; Lendahl, Urban; Tse, Gary; Louch, William E.; Chien, Kenneth R.

doi:10.1016/j.ymthe.2018.02.012

Cited by 45 publications

(42 citation statements)

References 58 publications

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“…The grafts from primed CPCs exhibited hPSC‐CMs with elongated morphology and aligned myofilaments in contrast to the more immature appearing circular clusters of hPSC‐CMs from untreated CPCs. We cannot exclude that longer in vivo follow‐up of animals would equalize certain of these differences, but the finding of accelerated differentiation of primed CPCs is consistent with the previously reported ability of later stage, committed CPCs to more readily differentiate into hPSC‐CMs in the kidney capsule in contrast to early stage CPCs . In addition, these results from the heterotopic kidney capsule transplant model agree with the observed in vitro effects of pIC and suggest that this strategy could have relevance for cell therapy applications.…”

Section: Resultssupporting

confidence: 85%

Epigenetic Priming of Human Pluripotent Stem Cell-Derived Cardiac Progenitor Cells Accelerates Cardiomyocyte Maturation

et al. 2019

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Human pluripotent stem cell‐derived cardiomyocytes (hPSC‐CMs) exhibit a fetal phenotype that limits in vitro and therapeutic applications. Strategies to promote cardiomyocyte maturation have focused interventions on differentiated hPSC‐CMs, but this study tests priming of early cardiac progenitor cells (CPCs) with polyinosinic‐polycytidylic acid (pIC) to accelerate cardiomyocyte maturation. CPCs were differentiated from hPSCs using a monolayer differentiation protocol with defined small molecule Wnt temporal modulation, and pIC was added during the formation of early CPCs. pIC priming did not alter the expression of cell surface markers for CPCs (>80% KDR+/PDGFRα+), expression of common cardiac transcription factors, or final purity of differentiated hPSC‐CMs (∼90%). However, CPC differentiation in basal medium revealed that pIC priming resulted in hPSC‐CMs with enhanced maturity manifested by increased cell size, greater contractility, faster electrical upstrokes, increased oxidative metabolism, and more mature sarcomeric structure and composition. To investigate the mechanisms of CPC priming, RNAseq revealed that cardiac progenitor‐stage pIC modulated early Notch signaling and cardiomyogenic transcriptional programs. Chromatin immunoprecipitation of CPCs showed that pIC treatment increased deposition of the H3K9ac activating epigenetic mark at core promoters of cardiac myofilament genes and the Notch ligand, JAG1. Inhibition of Notch signaling blocked the effects of pIC on differentiation and cardiomyocyte maturation. Furthermore, primed CPCs showed more robust formation of hPSC‐CMs grafts when transplanted to the NSGW mouse kidney capsule. Overall, epigenetic modulation of CPCs with pIC accelerates cardiomyocyte maturation enabling basic research applications and potential therapeutic uses. Stem Cells 2019;37:910–923

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Section: Resultssupporting

confidence: 85%

Epigenetic Priming of Human Pluripotent Stem Cell-Derived Cardiac Progenitor Cells Accelerates Cardiomyocyte Maturation

et al. 2019

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“…As established in a previous study in hESCs , in vitro cardiogenesis occurs via sequential distinct developmental stages, corresponding to the parental embryonic stem cells (day 0), primitive streak/early mesoderm (day 1), cardiac mesoderm (day 3), and cardiac progenitor/early CM stages (day 6). To understand the downstream effect of SMAD4 mutations in this sequential process of human in vitro cardiogenesis, we used RNA‐Seq to comprehensively compare the transcriptional profiles between the WT and the SMAD4 mutants at these stages.…”

Section: Resultsmentioning

confidence: 87%

SMAD4 Is Essential for Human Cardiac Mesodermal Precursor Cell Formation

Gruber

Chien

2018

Stem Cells

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Understanding stage‐specific molecular mechanisms of human cardiomyocyte (CM) progenitor formation and subsequent differentiation are critical to identify pathways that might lead to congenital cardiovascular defects and malformations. In particular, gene mutations in the transforming growth factor (TGF)β superfamily signaling pathways can cause human congenital heart defects, and murine loss of function studies of a central component in this pathway, Smad4, leads to early embryonic lethality. To define the role of SMAD4 at the earliest stages of human cardiogenesis, we generated SMAD4 mutant human embryonic stem cells (hESCs). Herein, we show that the loss of SMAD4 has no effect on hESC self‐renewal, or neuroectoderm formation, but is essential for the formation of cardiac mesoderm, with a subsequent complete loss of CM formation during human ES cell cardiogenesis. Via transcriptional profiling, we show that SMAD4 mutant cell lines fail to generate cardiac mesodermal precursors, clarifying a role of NODAL/SMAD4 signaling in cardiac mesodermal precursor formation via enhancing the expression of primitive streak genes. Since SMAD4 relative pathways have been linked to congenital malformations, it will become of interest to determine whether these may due, in part, to defective cell fate decision during cardiac mesodermal precursor formation. Stem Cells 2018 Stem Cells 2019;37:216–225

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“…Primary cardiomyocytes isolated from neonatal mice, rats, and chicken embryos were popular cell sources for in vitro cardiac models , but research based on these primary cells demonstrated that animal cell‐based models cannot truly recapitulate human physiology. Consequently, more sophisticated cell models were developed to create human‐like tissue models . However, establishing human models proved to be challenging as cardiac tissue or isolated cardiomyocytes from patients are difficult to obtain and cannot survive long‐term culture .…”

Section: Cardiac Disease Modeling—translation To the Clinical Settingmentioning

confidence: 99%

“…As a result, matured human cardiac organoids can be applied for high throughput screening. Alternatively, Foo et al have recently introduced a method for the generation of vascularized cardiac tissues by transplanting human stem cell‐derived cardiac precursors subcapsularly onto kidneys in mice . Furthermore, Lind et al demonstrated that the popular “Heart‐on‐a‐chip” concept can now be obtained by a combination of a 3D printed flexible chip and tissue engineering .…”

Section: Cardiac Tissue Engineeringmentioning

confidence: 99%

Concise Review: The Current State of Human In Vitro Cardiac Disease Modeling: A Focus on Gene Editing and Tissue Engineering

Hoes

Bömer

Meer

2018

Stem Cells Translational Medicine

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Until recently, in vivo and ex vivo experiments were the only means to determine factors and pathways involved in disease pathophysiology. After the generation of characterized human embryonic stem cell lines, human diseases could readily be studied in an extensively controllable setting. The introduction of human‐induced pluripotent stem cells, a decade ago, allowed the investigation of hereditary diseases in vitro. In the field of cardiology, diseases linked to known genes have successfully been studied, revealing novel disease mechanisms. The direct effects of various mutations leading to hypertrophic cardiomyopathy, dilated cardiomyopathy, arrythmogenic cardiomyopathy, or left ventricular noncompaction cardiomyopathy are discovered as a result of in vitro disease modeling. Researchers are currently applying more advanced techniques to unravel more complex phenotypes, resulting in state‐of‐the‐art models that better mimic in vivo physiology. The continued improvement of tissue engineering techniques and new insights into epigenetics resulted in more reliable and feasible platforms for disease modeling and the development of novel therapeutic strategies. The introduction of CRISPR‐Cas9 gene editing granted the ability to model diseases in vitro independent of induced pluripotent stem cells. In addition to highlighting recent developments in the field of human in vitro cardiomyopathy modeling, this review also aims to emphasize limitations that remain to be addressed; including residual somatic epigenetic signatures induced pluripotent stem cells, and modeling diseases with unknown genetic causes. Stem Cells Translational Medicine 2019;8:66–74

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Human ISL1+ Ventricular Progenitors Self-Assemble into an In Vivo Functional Heart Patch and Preserve Cardiac Function Post Infarction

Cited by 45 publications

References 58 publications

Epigenetic Priming of Human Pluripotent Stem Cell-Derived Cardiac Progenitor Cells Accelerates Cardiomyocyte Maturation

Epigenetic Priming of Human Pluripotent Stem Cell-Derived Cardiac Progenitor Cells Accelerates Cardiomyocyte Maturation

SMAD4 Is Essential for Human Cardiac Mesodermal Precursor Cell Formation

Concise Review: The Current State of Human In Vitro Cardiac Disease Modeling: A Focus on Gene Editing and Tissue Engineering

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