A series of robust genetic indicators for definitive identification of cardiomyocytes

Yan, Jianyun; Zhang, Lu; Sultana, Nishat; Oh, Jae Gyun; Wu, Bingruo; Hajjar, Roger J.; Zhou, Bin; Cai, Chen

doi:10.1016/j.yjmcc.2016.06.003

Cited by 11 publications

(11 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3A). Then, we treated cultured primary embryonic cardiomyocytes isolated from E13.5 Tnnt2 nGFP/+ hearts 43 with supernatants from either Hdac3 KO MECs or Hdac3 EV MECs, respectively. Hdac3 KO supernatant treatment resulted in significant decrease of the percentage of p-H3+ cardiomyocytes and the total number of cardiomyocytes, as compared to Hdac3 EV supernatant treatment (Fig.…”

Section: Resultsmentioning

confidence: 99%

Epicardial HDAC3 promotes myocardial growth through a novel microRNA pathway

Jang

Song

et al. 2021

Preprint

View full text Add to dashboard Cite

Rational: Establishment of the myocardial wall requires proper growth cues from nonmyocardial tissues. During heart development, the epicardium and epicardium-derived cells (EPDCs) instruct myocardial growth by secreting essential factors including fibroblast growth factor 9 (FGF9) and insulin-like growth factor 2 (IGF2). However, it is poorly understood how the epicardial secreted factors are regulated, in particular by chromatin modifications for myocardial formation. Objective: To understand whether and how histone deacetylase 3 (HDAC3) in the developing epicardium regulates myocardial growth. Methods and Results: We deleted Hdac3 in the developing murine epicardium and mutant hearts showed ventricular myocardial wall hypoplasia with reduction of EPDCs. The cultured embryonic cardiomyocytes with supernatants from Hdac3 knockout (KO) mouse epicardial cells (MECs) also showed decreased proliferation. Genome-wide transcriptomic analysis revealed that Fgf9 and Igf2 were significantly down-regulated in Hdac3 KO MECs. We further found that Fgf9 and Igf2 expression is dependent on HDAC3 deacetylase activity. The supplementation of FGF9 or IGF2 can rescue the myocardial proliferation defects treated by Hdac3 KO supernatant. Mechanistically, we identified that microRNA (miR)-322 and miR-503 were upregulated in Hdac3 KO MECs and Hdac3 epicardial KO hearts. Overexpression of miR-322 or miR-503 repressed FGF9 and IGF2 expression, while knockdown of miR-322 or miR-503 restored FGF9 and IGF2 expression in Hdac3 KO MECs. Conclusions: Our findings reveal a critical signaling pathway in which epicardial HDAC3 promotes compact myocardial growth by stimulating FGF9 and IGF2 through repressing miR-322/miR-503, providing novel insights in elucidating etiology of congenital heart defects, and conceptual strategies to promote myocardial regeneration.

show abstract

Section: Resultsmentioning

confidence: 99%

Epicardial HDAC3 promotes myocardial growth through a novel microRNA pathway

Jang

Song

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Therefore, we introduced a super-sensitive cardiomyocyte-specific reporter mouse model, cTnT nlacZ-H2B-GFP/+ and crossed it with Sca-1 MerCreMer/+ mice. The LoxP-nLacZ-4XPloyA-LoxP-H2B-GFP cassette was inserted into the cTnT start codon in cTnT nlacZ-H2B-GFP/+ mice 40 . Bright nuclear GFP (cTnT H2B-GFP ) was expressed when Cre activity was present in the myocardium or myocardial precursor cells (Figure 3 F).…”

Section: Resultsmentioning

confidence: 99%

Cardiac Sca-1 ⁺ Cells Are Not Intrinsic Stem Cells for Myocardial Development, Renewal, and Repair

et al. 2018

Self Cite

View full text Add to dashboard Cite

Background: For over a decade, Sca-1+ cells within the mouse heart have been widely recognized as a stem cell population with multipotency that can give rise to cardiomyocytes, endothelial cells and smooth muscle cells in vitro and after cardiac grafting. However, the developmental origin and authentic nature of these cells remain elusive. Methods: Here, we used a series of high-fidelity genetic mouse models to characterize the identity and regenerative potential of cardiac resident Sca-1+ cells. Results: With these novel genetic mouse models, we found that Sca-1 does not label cardiac precursor cells during early embryonic heart formation. Postnatal cardiac resident Sca-1+ cells are in fact a pure endothelial cell population. They retain endothelial properties and exhibit minimal cardiomyogenic potential during development, normal aging and upon ischemic injury. Conclusions: Our study provides definitive insights into the nature of cardiac resident Sca-1+ cells. The observations challenge the current dogma that cardiac resident Sca-1+ cells are intrinsic stem cells for myocardial development, renewal and repair and suggest that the mechanisms of transplanted Sca-1+ cells in heart repair need to be reassessed.

show abstract

“…However, we observed Cre activity in the hearts of Myh6 -Cre mice as early as E9.0 with m RNA expression detected at E8.5 by ISH, refuting this notion (Supplementary Figure S10). If loss of Cxadr in the heart is the driver of secondary placental defects, it is due to the wider expression of Tnnt2 -Cre throughout the myocardium compared with Myh6 -Cre (Yan et al., 2016), rather than differences in the developmental onset of Cre expression. This raises an interesting question, could the degree of cardiac dysfunction, due to variation in the percentage of cardiomyocytes that express Cxadr , result in the difference between embryonic lethality, as seen in Cxadr Δ/Δ(f) ;Tg Tnnt2 -Cre embryos, and cardiomyopathies like those exhibited in Cxadr Δ/Δ(f) ;Tg Myh6 -Cre adult mice?…”

Section: Discussionmentioning

confidence: 99%

Secondary Placental Defects in Cxadr Mutant Mice

2019

View full text Add to dashboard Cite

The Coxsackie virus and adenovirus receptor (CXADR) is an adhesion molecule known for its role in virus-cell interactions, epithelial integrity, and organogenesis. Loss of Cxadr causes numerous embryonic defects in mice, notably abnormal development of the cardiovascular system, and embryonic lethality. While CXADR expression has been reported in the placenta, the precise cellular localization and function within this tissue are unknown. Since impairments in placental development and function can cause secondary cardiovascular abnormalities, a phenomenon referred to as the placenta-heart axis, it is possible placental phenotypes in Cxadr mutant embryos may underlie the reported cardiovascular defects and embryonic lethality. In the current study, we determine the cellular localization of placental Cxadr expression and whether there are placental abnormalities in the absence of Cxadr . In the placenta, CXADR is expressed specifically by trophoblast labyrinth progenitors as well as cells of the visceral yolk sac (YS). In the absence of Cxadr , we observed altered expression of angiogenic factors coupled with poor expansion of trophoblast and fetal endothelial cell subpopulations, plus diminished placental transport. Unexpectedly, preserving endogenous trophoblast Cxadr expression revealed the placental defects to be secondary to primary embryonic and/or YS phenotypes. Moreover, further tissue-restricted deletions of Cxadr suggest that the secondary placental defects are likely influenced by embryonic lineages such as the fetal endothelium or those within the extraembryonic YS vascular plexus.

show abstract

A series of robust genetic indicators for definitive identification of cardiomyocytes

Cited by 11 publications

References 31 publications

Epicardial HDAC3 promotes myocardial growth through a novel microRNA pathway

Epicardial HDAC3 promotes myocardial growth through a novel microRNA pathway

Cardiac Sca-1 ⁺ Cells Are Not Intrinsic Stem Cells for Myocardial Development, Renewal, and Repair

Secondary Placental Defects in Cxadr Mutant Mice

Contact Info

Product

Resources

About

A series of robust genetic indicators for definitive identification of cardiomyocytes

Cited by 11 publications

References 31 publications

Epicardial HDAC3 promotes myocardial growth through a novel microRNA pathway

Epicardial HDAC3 promotes myocardial growth through a novel microRNA pathway

Cardiac Sca-1 + Cells Are Not Intrinsic Stem Cells for Myocardial Development, Renewal, and Repair

Secondary Placental Defects in Cxadr Mutant Mice

Contact Info

Product

Resources

About

Cardiac Sca-1 ⁺ Cells Are Not Intrinsic Stem Cells for Myocardial Development, Renewal, and Repair