Epicardial HDAC3 Promotes Myocardial Growth Through a Novel MicroRNA Pathway

Jang, Jihyun; Song, Guang; Pettit, Sarah M; Li, Qinshan; Song, Xiaosu; Cai, Chen-Leng; Kaushal, Sunjay; Li, Deqiang

doi:10.1161/circresaha.122.320785

Cited by 20 publications

(23 citation statements)

References 76 publications

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“…The latter appears to be key in achieving a high degree of morphological, molecular and functional self-patterning of the myocardium, which has so far been lacking in cardiac organoid models 5,6 . This allowed us to demonstrate that epicardial secretion of IGF2 promotes human myocardial compaction as it does in the mouse 3,33,36 . Single-cell transcriptomic analyses of human embryonic and adult heart tissue have provided precious insights into epicardial development, which were critical in verifying the validity of our in vitro model.…”

Section: Discussionmentioning

confidence: 94%

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Epicardioid single-cell genomics uncovers principles of human epicardium biology in heart development and disease

et al. 2023

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The epicardium, the mesothelial envelope of the vertebrate heart, is the source of multiple cardiac cell lineages during embryonic development and provides signals that are essential to myocardial growth and repair. Here we generate self-organizing human pluripotent stem cell-derived epicardioids that display retinoic acid-dependent morphological, molecular and functional patterning of the epicardium and myocardium typical of the left ventricular wall. By combining lineage tracing, single-cell transcriptomics and chromatin accessibility profiling, we describe the specification and differentiation process of different cell lineages in epicardioids and draw comparisons to human fetal development at the transcriptional and morphological levels. We then use epicardioids to investigate the functional cross-talk between cardiac cell types, gaining new insights into the role of IGF2/IGF1R and NRP2 signaling in human cardiogenesis. Finally, we show that epicardioids mimic the multicellular pathogenesis of congenital or stress-induced hypertrophy and fibrotic remodeling. As such, epicardioids offer a unique testing ground of epicardial activity in heart development, disease and regeneration.

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Section: Discussionmentioning

confidence: 94%

“…6a). We detected epicardial signals known to stimulate CM proliferation in the mouse, such as the secretion of IGF2 and fibronectin binding to integrin-β1 as well as the CXCL12-CXCR4 axis promoting coronary angiogenesis in zebrafish 3,[31][32][33] (Fig. 3b and Extended Data Fig.…”

Section: Investigating the Functional Cross-talk Between Cardiac Cellsmentioning

confidence: 99%

Epicardioid single-cell genomics uncovers principles of human epicardium biology in heart development and disease

et al. 2023

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“…In heart, the absence of HDAC3 in the embryo results in severe hypertrophic cardiomyopathy and lethality by 3 to 4 months [ 28 ]. In the developing murine epicardium, the loss of HDAC3 causes ventricular myocardial wall hypoplasia with reduction of epicardium-derived cells [ 29 ]. In neural progenitor cells (NPCs) of the central nervous system, HDAC3 deficiency can impair neuronal migration and cortical lamination, resulting in serious lethality within 16 hours after birth [ 30 ].…”

Section: Overview Of Hdac3mentioning

confidence: 99%

“…Interestingly, although most of the current studies show that HDAC3 seems to play an evil role in many cardiovascular diseases, and pharmacological or genetic inhibition of HDAC3 can improve MI, myocardial fibrosis, and myocardial remodeling, HDAC3 also is essential for heart development. Many studies have proved that the deletion of HDAC3 causes the loss of ventricular structure and developmental abnormalities of the heart [ 29 , 126 ]. This seemingly contradictory conclusion is associated with the important non-enzymatic action of HDAC3, some studies also finding that HDAC3 deacetylase activity is dispensable for repression of myocyte differentiation [ 126 ].…”

Section: The Role Of Hdac3 and Its Inhibitors In Chronic Diseasesmentioning

confidence: 99%

The role of HDAC3 and its inhibitors in regulation of oxidative stress and chronic diseases

Liu

Geng

et al. 2023

Cell Death Discov.

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HDAC3 is a specific and crucial member of the HDAC family. It is required for embryonic growth, development, and physiological function. The regulation of oxidative stress is an important factor in intracellular homeostasis and signal transduction. Currently, HDAC3 has been found to regulate several oxidative stress-related processes and molecules dependent on its deacetylase and non-enzymatic activities. In this review, we comprehensively summarize the knowledge of the relationship of HDAC3 with mitochondria function and metabolism, ROS-produced enzymes, antioxidant enzymes, and oxidative stress-associated transcription factors. We also discuss the role of HDAC3 and its inhibitors in some chronic cardiovascular, kidney, and neurodegenerative diseases. Due to the simultaneous existence of enzyme activity and non-enzyme activity, HDAC3 and the development of its selective inhibitors still need further exploration in the future.

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“…MCECs were cultured in 10% fetal bovine serum (FBS) supplemented DMEM at 37°C in a humidified incubator with 5% CO2. To generate stable Hdac3 KO MCECs, as previously described 26…”

Section: Endothelial Cell Culture Transient Transfection Lentiviral I...mentioning

confidence: 99%

Endocardial HDAC3 is required for myocardial trabeculation

Jang

Bentsen

Kim

et al. 2023

Preprint

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Background: Trabeculation, a key process in early heart development, is the formation of myocardial trabecular meshwork. The failure of trabeculation often leads to embryonic lethality. Support from endocardial cells, including the secretion of extracellular matrix (ECM) and growth factors is critical for trabeculation; however, it is unknown how the secretion of ECM and growth factors is initiated and regulated by endocardial cells. Methods: Various cellular and mouse models in conjunction with biochemical and molecular tools were employed to study the role of histone deacetylase 3 (HDAC3) in the developing endocardium. Results: We found that genetic deletion of Hdac3 in endocardial cells in mice resulted in early embryo lethality presenting as a hypotrabeculation cardiac phenotype. Single cell RNA sequencing identified several ECM components including collagens that were significantly downregulated in Hdac3 knockout (KO) endocardial cells. When cultured with supernatant from Hdac3 KO mouse cardiac endothelial cells (MCECs), wild-type mouse embryonic cardiomyocytes showed decreased proliferation, suggesting that growth signaling from Hdac3 KO MCECs is disrupted. Subsequent transcriptomic analysis revealed that transforming growth factor β3 (TGFβ3) was significantly downregulated in Hdac3 KO MCECs and Hdac3 cardiac endothelial KO hearts. Mechanistically, we identified that microRNA (miR)-129-5p was significantly upregulated in Hdac3 KO MCECs and Hdac3 cardiac endothelial KO hearts. Overexpression of miR-129-5p repressed Tgfβ3 expression in wild-type MCECs, whereas knockdown of miR-129-5p restored Tgfβ3 expression in Hdac3 KO MCECs. Conclusion: Our findings reveal a critical signaling pathway in which endocardial HDAC3 promotes trabecular myocardium growth by stimulating TGFβ signaling through repressing miR-129-5p, providing novel insights into the etiology of congenital heart disease and conceptual strategies to promote myocardial regeneration.

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Epicardial HDAC3 Promotes Myocardial Growth Through a Novel MicroRNA Pathway

Cited by 20 publications

References 76 publications

Epicardioid single-cell genomics uncovers principles of human epicardium biology in heart development and disease

Epicardioid single-cell genomics uncovers principles of human epicardium biology in heart development and disease

The role of HDAC3 and its inhibitors in regulation of oxidative stress and chronic diseases

Endocardial HDAC3 is required for myocardial trabeculation

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