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  • 1
    Online Resource
    Online Resource
    Abstract 17503: ETV2 Functions as a Pioneer Factor and Regulates the Endothelial Lineage
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Circulation Vol. 142, No. Suppl_3 ( 2020-11-17)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 142, No. Suppl_3 ( 2020-11-17)
    Abstract: Background: Genetic mutations perturb the multipotent progenitors, which results in congenital cardiovascular disease. Therefore, it is essential to decipher the pioneer factors and the regulatory pathways that govern the specification and differentiation of mesodermal progenitors and use this information to develop targeted therapies to promote cardiovascular regeneration. Etv2 as an essential transcription factor for the development of cardiac, endothelial and hematopoietic lineages. In the present study, we used ES/EB differentiation and MEF reprogramming systems, to define Etv2 as a novel pioneer factor that relaxes the closed chromatin and drives endothelial development. Results: Using the iHA-Etv2 ES cell line, we engineered a mouse that inducibly overexpresses ETV2. The bulk RNA-seq, single cell RNA-seq data and ATAC-seq experiments showed that inducing Etv2 in MEFs and ES/EBs activated the downstream endothelial marker genes and promoted the development of endothelial lineages, supporting the notion that Etv2 functioned as a master regulator to drive the endothelial lineage development in different cellular contexts. We found that similar to other known pioneer factors, Etv2 was intrinsically able to target and bind the nucleosomes, and this capability appeared to be independent of the cellular context. To further define the mechanism, we performed Etv2, Brg1 and H3K27ac ChIP-seq analyses during MEF reprogramming and ES/EB differentiation. We found that Brg1 maintains and stabilizes the binding of Etv2 on the nucleosome, and Etv2 requires Brg1 to activate downstream genes during reprograming. Conclusion: In these studies, we defined Etv2 as a novel pioneer factor that relaxed the closed chromatin and promoted the endothelial lineage in both ES/EB differentiation and MEF reprogramming. The definition of these mechanisms will enhance our understanding of cardiovascular development and regeneration and serve as a platform for therapeutic applications for patients with congenital or aging related cardiovascular diseases.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.142.suppl_3.17503
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 1466401-X
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  • 2
    Online Resource
    Online Resource
    Emerging technologies and ethics—exogenic chimeric humanized organs
    Elsevier BV ; 2022
    In:  American Journal of Transplantation Vol. 22, No. 12 ( 2022-12), p. 2786-2790
    Details
    In: American Journal of Transplantation, Elsevier BV, Vol. 22, No. 12 ( 2022-12), p. 2786-2790
    Type of Medium: Online Resource
    ISSN: 1600-6135
    URL: Article
    DOI: 10.1111/ajt.17188
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 2045621-9
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  • 3
    Online Resource
    Online Resource
    FOXK1 regulates Wnt signalling to promote cardiogenesis
    Oxford University Press (OUP) ; 2023
    In:  Cardiovascular Research Vol. 119, No. 8 ( 2023-07-06), p. 1728-1739
    Details
    In: Cardiovascular Research, Oxford University Press (OUP), Vol. 119, No. 8 ( 2023-07-06), p. 1728-1739
    Abstract: Congenital heart disease (CHD) is the most common genetic birth defect, which has considerable morbidity and mortality. We focused on deciphering key regulators that govern cardiac progenitors and cardiogenesis. FOXK1 is a forkhead/winged helix transcription factor known to regulate cell cycle kinetics and is restricted to mesodermal progenitors, somites, and heart. In the present study, we define an essential role for FOXK1 during cardiovascular development. Methods and results We used the mouse embryoid body system to differentiate control and Foxk1 KO embryonic stem cells into mesodermal, cardiac progenitor cells and mature cardiac cells. Using flow cytometry, immunohistochemistry, cardiac beating, transcriptional and chromatin immunoprecipitation quantitative polymerase chain reaction assays, bulk RNA sequencing (RNAseq) and assay for transposase-accessible chromatin using sequencing (ATACseq) analyses, FOXK1 was observed to be an important regulator of cardiogenesis. Flow cytometry analyses revealed perturbed cardiogenesis in Foxk1 KO embryoid bodies (EBs). Bulk RNAseq analysis at two developmental stages showed a significant reduction of the cardiac molecular program in Foxk1 KO EBs compared to the control EBs. ATACseq analysis during EB differentiation demonstrated that the chromatin landscape nearby known important regulators of cardiogenesis was significantly relaxed in control EBs compared to Foxk1 KO EBs. Furthermore, we demonstrated that in the absence of FOXK1, cardiac differentiation was markedly impaired by assaying for cardiac Troponin T expression and cardiac contractility. We demonstrate that FOXK1 is an important regulator of cardiogenesis by repressing the Wnt/β-catenin signalling pathway and thereby promoting differentiation. Conclusion These results identify FOXK1 as an essential transcriptional and epigenetic regulator of cardiovascular development. Mechanistically, FOXK1 represses Wnt signalling to promote the development of cardiac progenitor cells.
    Type of Medium: Online Resource
    ISSN: 0008-6363 , 1755-3245
    URL: Article
    DOI: 10.1093/cvr/cvad054
    RVK:
    WA 15000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1499917-1
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  • 4
    Online Resource
    Online Resource
    Neonatal Cardiac Scaffolds: Novel Matrices for Regenerative Studies
    MyJove Corporation ; 2016
    In:  Journal of Visualized Experiments , No. 117 ( 2016-11-05)
    Details
    In: Journal of Visualized Experiments, MyJove Corporation, , No. 117 ( 2016-11-05)
    Type of Medium: Online Resource
    ISSN: 1940-087X
    URL: Article
    DOI: 10.3791/54459
    Language: English
    Publisher: MyJove Corporation
    Publication Date: 2016
    detail.hit.zdb_id: 2259946-0
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  • 5
    Online Resource
    Online Resource
    Blastocyst complementation and interspecies chimeras in gene edited pigs
    Frontiers Media SA ; 2022
    In:  Frontiers in Cell and Developmental Biology Vol. 10 ( 2022-12-8)
    Details
    In: Frontiers in Cell and Developmental Biology, Frontiers Media SA, Vol. 10 ( 2022-12-8)
    Abstract: The only curative therapy for many endstage diseases is allograft organ transplantation. Due to the limited supply of donor organs, relatively few patients are recipients of a transplanted organ. Therefore, new strategies are warranted to address this unmet need. Using gene editing technologies, somatic cell nuclear transfer and human induced pluripotent stem cell technologies, interspecies chimeric organs have been pursued with promising results. In this review, we highlight the overall technical strategy, the successful early results and the hurdles that need to be addressed in order for these approaches to produce a successful organ that could be transplanted in patients with endstage diseases.
    Type of Medium: Online Resource
    ISSN: 2296-634X
    URL: Article
    DOI: 10.3389/fcell.2022.1065536
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2737824-X
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  • 6
    Online Resource
    Online Resource
    Hypoxia-Inducible Factor-2α Transactivates Abcg2 and Promotes Cytoprotection in Cardiac Side Population Cells
    Ovid Technologies (Wolters Kluwer Health) ; 2008
    In:  Circulation Research Vol. 102, No. 9 ( 2008-05-09), p. 1075-1081
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 102, No. 9 ( 2008-05-09), p. 1075-1081
    Abstract: Stem and progenitor cell populations occupy a specialized niche and are consequently exposed to hypoxic as well as oxidative stresses. We have previously established that the multidrug resistance protein Abcg2 is the molecular determinant of the side population (SP) progenitor cell population. We observed that the cardiac SP cells increase in number more than 3-fold within 3 days of injury. Transcriptome analysis of the SP cells isolated from the injured adult murine heart reveals increased expression of cytoprotective transcripts. Overexpression of Abcg2 results in an increased ability to consume hydrogen peroxide and is associated with increased levels of α-glutathione reductase protein expression. Importantly, overexpression of Abcg2 also conferred a cell survival benefit following exposure to hydrogen peroxide. To further examine the molecular regulation of the Abcg2 gene, we demonstrated that hypoxia-inducible factor (HIF)-2α binds an evolutionary conserved HIF-2α response element in the murine Abcg2 promoter. Transcriptional assays reveal a dose-dependent activation of Abcg2 expression by HIF-2α. These results support the hypothesis that Abcg2 is a direct downstream target of HIF-2α which functions with other factors to initiate a cytoprotective program for this progenitor SP cell population that resides in the adult heart.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/CIRCRESAHA.107.161729
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2008
    detail.hit.zdb_id: 1467838-X
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  • 7
    Online Resource
    Online Resource
    Abstract 370: Hedgehog Signaling Regulates Cardiac Regeneration in vivo
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Circulation Research Vol. 119, No. suppl_1 ( 2016-07-22)
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 119, No. suppl_1 ( 2016-07-22)
    Abstract: The adult mammalian heart has a limited regenerative capacity due primarily to reduced cardiomyocyte (CM) proliferation. Here, we demonstrated hedgehog (HH) signaling pathway as an essential regulator of heart regeneration and CM proliferation. We undertook genome-wide screening using a novel algorithm, bootstrap, which showed an induction of HH signals in the regenerating newt heart. Blockade of HH signaling in the resected newt heart resulted in complete ablation of cardiac regeneration and scar formation. EdU-labeling revealed that inhibition of the HH pathway significantly reduced CM proliferation by 3-fold (n=4 at each time period post-injury). In mammals, cardiac specific loss- and gain-of-function of HH signals demonstrated its role in CM proliferation and regeneration in the postnatal heart. Genetic deletion of floxed-Smoothened ( Smo L/L ) allele at postnatal day 2 (P2) inhibited neonatal heart regeneration with impaired cardiac function and scarring following injury. Conversely, induction of constitutively active Smoothened (SmoM2) at P7 stimulated CM proliferation by 2.5-fold (n=3) and regeneration after myocardial infarction during the non-regenerative window. Lineage-tracing experiments showed that activation of Smo contributed to heart regeneration by promoting proliferation of the pre-existing cardiomyocytes. Activation of HH signals in the cultured CM at P1 and P7 showed an increased proliferative response by 2- and 3-fold (n=4; 1900 cells evaluated for each condition), respectively. Mechanistically, ChIP-seq analysis revealed that HH signals promoted the proliferative program by directly regulating the expression of cyclin-dependent kinases including cyclinD2, cyclinE1 and Cdc7. Finally, activation of HH signaling in the terminally differentiated hiPSC-derived CM resulted in an increase in the number of α-Actinin + /EdU + and α-Actinin + /Ki67 + cells by 2.5-fold (n=3; 645 cells assessed for each condition) and 3-fold (n=3; 685 cells assessed for each condition), respectively. These studies defined an evolutionarily conserved function of HH signaling from newt to mouse to human, as a key regulator of cardiomyocyte proliferation and regeneration that may serve as a platform for regenerative therapies.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/res.119.suppl_1.370
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
    detail.hit.zdb_id: 1467838-X
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  • 8
    Online Resource
    Online Resource
    Abstract 98: Embryonic Extracellular Matrix and Cell Fate Determination
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Circulation Research Vol. 117, No. suppl_1 ( 2015-07-17)
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 117, No. suppl_1 ( 2015-07-17)
    Abstract: Background - The determination of cell fate during development is governed by intrinsic factors, but also by interaction with the milieu in which they reside. The extracellular matrix (ECM) from rapidly developing tissue should form a rich signaling environment for cellular proliferation and differentiation. Hypothesis - Murine embryonic ECM can be prepared by detergent decellularization that is morphologically preserved, biocompatible for cell culture, and at E13.5 substantial enough to permit vascular catheterization and recellularization by perfusion. Methods and Results - To test the contribution of embryonic extracellular matrix (ECM) to the determination of cell fate, we undertook isolation of ECM from developing murine embryos. Triton X-100 and SDS detergent decellularization were used to isolate ECM from E10.5 and E13.5 embryos. Acellularity was confirmed by pico-green DNA assay (98.7 % ± 0.95 of DNA removed compared to control), as well as the lack of visible nuclei by H & E and DAPI histology. The matrix scaffolds were washed thoroughly with PBS and culture media to return them to a biocompatible state. Murine embryonic stem cells (mESC) modified to express EGFP were cultured on the exterior or the interior of the ECM scaffolds. mESCs seeded on the exterior of the E10.5 scaffolds or perfused through the E13.5 umbilical vasculature were highly adherent and proliferative during the 17 day culture period as evidenced by fluorescent microscopy. Perfused mESCs exhibited engrafted in the heart, liver, and vascular conduit E13.5 matrix 2 days post-infusion. Histology confirmed the attachment and morphologic alteration of the cultured cells on the exterior of the E10.5 ECM and presence of the perfused cells in the E13.5 embryo matrix interior. Conclusion - Biocompatible, acellular morphologically preserved embryonic ECM can be extracted from E10.5 and E13.5 murine embryos. By E13.5 the structural integrity of the acellular matrix can sustain vascular perfusion for delivery of mESCs to internal organoid structures. These ECM preparations support the proliferation and maintenance of mESCs externally and internally.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/res.117.suppl_1.98
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 1467838-X
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  • 9
    Online Resource
    Online Resource
    Abstract 4: Porcine Parthenotes as a Model to Evaluate Developmental Potential of Human Inducible Pluripotent Stem Cells
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Circulation Research Vol. 117, No. suppl_1 ( 2015-07-17)
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 117, No. suppl_1 ( 2015-07-17)
    Abstract: The use of human induced pluripotent stem cells (hiPSCs) has tremendous potential for regenerative medicine by providing an unlimited source of personalized cells. A number of protocols have been established for efficient differentiation of hiPSCs to the desired lineage in vitro, such as cardiomyocytes and blood. However, the field lacks an in vivo system to evaluate the differentiation potential and quality of hiPSCs. Developmental potential of stem cells derived from experimental animals can be readily assessed by generating blastocyst chimeras and examination of the contribution to the embryos, or by the potential of teratoma formation. However, this is not possible in the case of humans. As a potential solution for this issue, we examined whether porcine parthenotes could be used as an experimental model to test the developmental potential of the hiPSCs. Parthenotes are generated by electrical activation of the oocytes collected at the abattoir and will develop up to gestational day 53 if transferred to a pseudo-pregnant sow. The embryonic culture conditions have also been established and the zygotes can develop normally to the expanded blastocyst stage (day 7 post fertilization/activation), in vitro. We took advantage of this in vitro system and examined the ability of hiPSCs to proliferate and integrate into the parthenogenetic embryos. Parthenogenetic embryos were injected with ten undifferentiated hiPSCs at day 4 (8 cell ~ morula stage) and cultured up to 72 hours. During this period, parthenotes underwent blastocoel cavity formation and hatching. Cell tracing experiments demonstrated that hiPSCs proliferated and integrated into the parthenotes. They retained pluripotency marker expression during this period. hiPSCs and their derivatives were found both in trophoectoderm and embryo proper. We further observed that the hiPSCs underwent cellular proliferation and promoted developmental progression of the parthenote in vitro. In summary, the porcine parthenote model system is an efficient high throughput system to examine the developmental capacity of human stem cell populations.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/res.117.suppl_1.4
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 1467838-X
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  • 10
    Online Resource
    Online Resource
    Cardiac Xenotransplantation: Clinical Impact of Science and Discovery
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Circulation Vol. 146, No. 13 ( 2022-09-27), p. 961-963
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 146, No. 13 ( 2022-09-27), p. 961-963
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.122.059191
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1466401-X
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