Gata4-Dependent Differentiation of c-Kit
            <sup>+</sup>
            –Derived Endothelial Cells Underlies Artefactual Cardiomyocyte Regeneration in the Heart

Maliken, Bryan D.; Kanisicak, Onur; Karch, Jason; Khalil, Hadi; Fu, Xing; Boyer, Justin G.; Prasad, Vikram; Zheng, Yi; Molkentin, Jeffery D.

doi:10.1161/circulationaha.118.033703

Cited by 35 publications

(39 citation statements)

References 60 publications

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“…Mishra et al have demonstrated that progenitor cells isolated from the atria of patients with congenital heart disease showed the highest expression of the stem cell markers c-kit and Nkx2.5 in the neonatal age group (compared to infants and older children), and that this cell content directly correlated to their regenerative potential in mouse infarct models [ 5 ]. Recent work using kit allele lineage tracing has questioned the capacity of c-kit-positive CPCs to generate de novo cardiomyocytes [ 6 ], indicating instead that endothelial cells represent the principal fate of kit lineage-traced cells [ 7 ]. On the other hand, Ellison et al provided evidence based on genetic murine models and cell transplantation experiments that endogenous c-kit-positive cells cardiac stem cells are capable of generating new cardiomyocytes that are necessary and sufficient for myocardial repair [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Cardiac regenerative capacity is age- and disease-dependent in childhood heart disease

et al. 2018

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ObjectiveWe sought to define the intrinsic stem cell capacity in pediatric heart lesions, and the effects of diagnosis and of age, in order to inform evidence-based use of potential autologous stem cell sources for regenerative medicine therapy.MethodsVentricular explants derived from patients with hypoplastic left heart syndrome (HLHS), tetralogy of Fallot (TF), dilated cardiomyopathy (DCM) and ventricular septal defect (VSD) were analyzed following standard in vitro culture conditions, which yielded cardiospheres (C-spheres), indicative of endogenous stem cell capacity. C-sphere counts generated per 5 mm3 tissue explant and the presence of cardiac progenitor cells were correlated to patient age, diagnosis and echocardiographic function.ResultsCardiac explants from patients less than one year of age with TF and DCM robustly generated c-kit- and/or vimentin-positive cardiac mesenchymal cells (CMCs), populating spontaneously forming C-spheres. Beyond one year of age, there was a marked reduction or absence of cardiac explant-derivable cardiac stem cell content in patients with TF, VSD and DCM. Stem cell content in HLHS and DCM strongly correlated to the echocardiographic function in the corresponding ventricular chamber, with better echocardiographic function correlating to a more robust regenerative cellular content.ConclusionsWe conclude that autologous cardiomyogenic potential in pediatric heart lesions is robust during the first year of life and uniformly declines thereafter. Depletion of stem cell content occurs at an earlier age in HLHS with the onset of ventricular failure in a chamber-specific pattern that correlates directly to ventricular dysfunction. These data suggest that regenerative therapies using autologous cellular sources should be implemented in the neonatal period before the potentially rapid onset of single ventricle failure in HLHS or the evolution of biventricular failure in DCM.

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Section: Introductionmentioning

confidence: 99%

Cardiac regenerative capacity is age- and disease-dependent in childhood heart disease

et al. 2018

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“…There have been several studies reporting some key TFs of cardiac regeneration validated via observation of heart regeneration after manipulating the corresponding gene expression in a myocardial infarction mouse model or in a cardiac apex resection mouse model (Tao et al, ; Xiang et al, ; Maliken et al, ). TBX20 is one of these known key TFs of cardiac regeneration, and we also identified this protein in our study.…”

Section: Discussionmentioning

confidence: 99%

Proteomic profiling of key transcription factors in the process of neonatal mouse cardiac regeneration capacity loss

Wang

Nie

et al. 2019

Cell Biology International

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The heart lacks complete regeneration capacity. In mice, the cardiac apex can regenerate 1 day after birth, although 7 days after birth the repair occurs with a fibrous scar. However, the key transcription factors (TFs) related to this loss of regeneration capacity remain largely unknown. We aimed to find candidates for key TFs using proteomic profiling and comparison during loss of neonatal mouse cardiac regeneration capacity, with preliminary validation using western blotting (WB) and real-time quantitative polymerase chain reaction (RT-qPCR). A total of 69 common discrepant TFs with similar variation trends in two TF response element experiments were identified, 18 of which were matched to known key signaling pathways of cardiac regeneration after pathway enrichment of downstream genes. Validation using RT-qPCR-selected DACH1, RBL1 (P107), and TBX20, and further validation with WB-selected RBL1 (P107) and TBX20. We therefore identified two candidates for key TFs in the loss of mouse cardiac apex regeneration capacity. TBX20 has been biologically validated, and RBL1 (P107) needs to be validated in the future.Abbreviations: catTFREs, concatenated tandem array of 50 consensus TFREs; FOT, frequency of total; LC-MS, nano-liquid chromatography/tandem mass spectrometry; RT-qPCR, real-time quantitative polymerase chain reaction; TFRE, TF response elements; TFs, transcription factors; WB, western blotting First author under standardized training of residents at West China hospital.

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“…Therefore, c-kit was used as a cardiac progenitor cell marker [ 116 , 117 ]. Recently, several studies revealed that the contribution of c-kit+ cells to the generation of cardiomyocytes is insignificant due to their heterogeneous nature [ 117 , 118 , 119 ].…”

Section: Genetically Modified Stem Cell For MI Treatmentmentioning

confidence: 99%

Preconditioned and Genetically Modified Stem Cells for Myocardial Infarction Treatment

Raziyeva

Smagulova

Kim

et al. 2020

IJMS

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Ischemic heart disease and myocardial infarction remain leading causes of mortality worldwide. Existing myocardial infarction treatments are incapable of fully repairing and regenerating the infarcted myocardium. Stem cell transplantation therapy has demonstrated promising results in improving heart function following myocardial infarction. However, poor cell survival and low engraftment at the harsh and hostile environment at the site of infarction limit the regeneration potential of stem cells. Preconditioning with various physical and chemical factors, as well as genetic modification and cellular reprogramming, are strategies that could potentially optimize stem cell transplantation therapy for clinical application. In this review, we discuss the most up-to-date findings related to utilizing preconditioned stem cells for myocardial infarction treatment, focusing mainly on preconditioning with hypoxia, growth factors, drugs, and biological agents. Furthermore, genetic manipulations on stem cells, such as the overexpression of specific proteins, regulation of microRNAs, and cellular reprogramming to improve their efficiency in myocardial infarction treatment, are discussed as well.

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Gata4-Dependent Differentiation of c-Kit ⁺ –Derived Endothelial Cells Underlies Artefactual Cardiomyocyte Regeneration in the Heart

Abstract: Supplemental Digital Content is available in the text.

Cited by 35 publications

References 60 publications

Cardiac regenerative capacity is age- and disease-dependent in childhood heart disease

Cardiac regenerative capacity is age- and disease-dependent in childhood heart disease

Proteomic profiling of key transcription factors in the process of neonatal mouse cardiac regeneration capacity loss

Preconditioned and Genetically Modified Stem Cells for Myocardial Infarction Treatment

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Gata4-Dependent Differentiation of c-Kit + –Derived Endothelial Cells Underlies Artefactual Cardiomyocyte Regeneration in the Heart

Abstract: Supplemental Digital Content is available in the text.

Cited by 35 publications

References 60 publications

Cardiac regenerative capacity is age- and disease-dependent in childhood heart disease

Cardiac regenerative capacity is age- and disease-dependent in childhood heart disease

Proteomic profiling of key transcription factors in the process of neonatal mouse cardiac regeneration capacity loss

Preconditioned and Genetically Modified Stem Cells for Myocardial Infarction Treatment

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Product

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Gata4-Dependent Differentiation of c-Kit ⁺ –Derived Endothelial Cells Underlies Artefactual Cardiomyocyte Regeneration in the Heart