Disruption of spatiotemporal hypoxic signaling causes congenital heart disease in mice

Yuan, Xuejun; Qi, Hui; Li, Xiang; Wu, Fan; Fang, Jian; Bober, Eva; Dobreva, Gergana; Zhou, Yonggang; Braun, Thomas

doi:10.1172/jci88725

Cited by 37 publications

(67 citation statements)

References 60 publications

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“…2f). This pattern suggests that Nkx2-5 is associated with myogenic differentiation while Isl1 is linked to the maintenance of progenitor cell multipotency, which is consistent with previous models [10,36,37].…”

Section: Single Cell Transcriptomics Reveals Heterogeneity Of Cardiacsupporting

confidence: 91%

“…Isl1 is expressed in cardiac progenitor cells (CPC) of the SHF, although a broader, transient expression has been noted in the anterior intraembryonic coelomic walls and proximal head mesenchyme encompassing both the FHF and the SHF [7,8]. However, efficient nGFP labeling of CPC is only achieved in the SHF, making the Isl1 nGFP/+ knock-in reporter mouse line a reliable source for isolation of SHF cells [9,10]. In contrast, Nkx2-5 expression marks cells of both the FHF and SHF including the cardiac crescent and the pharyngeal mesoderm [1,7,11].…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, Nkx2-5 expression marks cells of both the FHF and SHF including the cardiac crescent and the pharyngeal mesoderm [1,7,11]. Although transient co-expression of Isl1 and Nkx2-5 has been observed, several lines of evidence indicate that Isl1 and Nkx2-5 suppress each other thereby allowing expansion of Isl1 + CPC and differentiation into Nkx2-5 + cardiomyocytes [7,10].…”

Section: Discussionmentioning

confidence: 99%

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Single cell RNA-seq and ATAC-seq indicate critical roles of Isl1 and Nkx2-5 for cardiac progenitor cell transition states and lineage settlement

Jia

Preussner

Guenther

et al. 2017

Preprint

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SUMMARYFormation and segregation of cell lineages building the vertebrate heart have been studied extensively by genetic cell tracing techniques and by analysis of single marker gene expression but the underlying gene regulatory networks driving cell fate transitions during early cardiogenesis are only partially understood. Here, we comprehensively characterized mouse cardiac progenitor cells (CPC) marked by Nkx2-5 and Isl1 expression from E7.5 to E9.5 using single-cell RNA sequencing. By leveraging on cell-to-cell heterogeneity, we identified different previously unknown cardiac sub-populations. Reconstruction of the developmental trajectory revealed that Isl1+ CPC represent a transitional cell population maintaining a prolonged multipotent state, whereas extended expression of Nkx2-5 commits CPC to a unidirectional cardiomyocyte fate. Furthermore, we show that CPC fate transitions are associated with distinct open chromatin states, which critically depend on Isl1 and Nkx2-5. Our data provide a model of transcriptional and epigenetic regulations during cardiac progenitor cell fate decisions at single-cell resolution.

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Section: Single Cell Transcriptomics Reveals Heterogeneity Of Cardiacsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Single cell RNA-seq and ATAC-seq indicate critical roles of Isl1 and Nkx2-5 for cardiac progenitor cell transition states and lineage settlement

Jia

Preussner

Guenther

et al. 2017

Preprint

Self Cite

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“…However, cardiogenesis can result in malformations, with congenital heart defects being present in 1% of live births. Several factors have been involved in developmental cardiac failure, and among them hypoxia, or low oxygen tensions, has been described as an environmental factor of cardiac malformations during pregnancy [4]. Hypoxia-Inducible Factors (HIFs) are known to mediate a well-characterized transcriptional response to hypoxia.…”

Section: Introductionmentioning

confidence: 99%

“…In addition to the existence of hypoxic areas during heart development [4,8], it has been described that chronic exposure of pregnant females to 8% oxygen causes embryonic myocardial thinning, epicardial detachment and death [9] and global deletion of different components of the hypoxia pathway display cardiovascular phenotypes [10]. Moreover, geneticbased overactivation of HIF signaling by inactivation of Vhl gene in cardiac cells using different drivers (Mlc2vCre, Nkx2.5Cre) causes morphological, metabolic and functional cardiac alterations that results in embryonic lethality [11,12].…”

Section: Introductionmentioning

confidence: 99%

Metabolic reprogramming from glycolysis to amino acid utilization in cardiac HIF1α deficient mice

Menendez-Montes

Escobar

Palacios

et al. 2019

Preprint

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Rationale.Hypoxia is an important environmental cue implicated in several physiopathological processes, including heart development. Several mouse models of activation or inhibition of hypoxia have been previously described. While gain of function models have been extensively characterized and indicate that HIF1 signaling needs to be tightly regulated to ensure a proper cardiac development, there is lack of consensus in the field about the functional outcomes of HIF1α loss.Objective. In this study, we aim to assess the consequences of cardiac deletion of HIF1α during heart development and identify the cardiac adaptations to HIF1 loss. Methods and Results.Here, we used a conditional deletion model of Hif1a in NKX2.5 + cardiac progenitors. By a combination of histology, electron microscopy, massive gene expression studies, proteomics, metabolomics and cardiac imaging, we found that HIF1α is dispensable for cardiac development. Hif1a loss results in glycolytic inhibition in the embryonic heart without affecting normal cardiac growth. However, together with a premature increase in mitochondrial number by E12.5, we found global upregulation of amino acid transport and catabolic processes. Interestingly, this amino acid catabolism activation is transient and does not preclude the normal cardiac metabolic switch towards fatty acid oxidation (FAO) after E14.5. Moreover, Hif1a loss is accompanied by an increase in ATF4, described as an important regulator of several amino acid transporters. Conclusions.Our data indicate that HIF1α is not required for normal cardiac development and suggest that additional mechanisms can compensate Hif1a loss. Moreover, our results reveal the metabolic flexibility of the embryonic heart at early stages of development, showing the capacity of the myocardium to adapt its energy source to satisfy the energetic and building blocks demands to achieve normal cardiac growth and function. This metabolic reprograming might be relevant in the setting of adult cardiac failure.

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Early Gestational Hypoxia and Adverse Developmental Outcomes

Ritchie

Oakes

Kennedy

et al. 2017

Birth Defects Research

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Hypoxia is a normal and essential part of embryonic development. However, this state may leave the embryo vulnerable to damage when oxygen supply is disturbed. Embryofetal response to hypoxia is dependent on duration and depth of hypoxia, as well as developmental stage. Early postimplantation rat embryos were resilient to hypoxia, with many surviving up to 1.5 hr of uterine clamping, while most mid-gestation embryos were dead after 1 hour of clamping. Survivors were small and many had a range of defects, principally terminal transverse limb reduction defects. Similar patterns of malformations occurred when embryonic hypoxia was induced by maternal hypoxia, interruption of uteroplacental flow, or perfusion and embryonic bradycardia. There is good evidence that high altitude pregnancies are associated with smaller babies and increased risk of some malformations, but these results are complicated by increased risk of pre-eclampsia. Early onset pre-eclampsia itself is associated with small for dates and increased risk of atrio-ventricular septal defects. Limb defects have clearly been associated with chorionic villus sampling, cocaine, and misoprostol use. Similar defects are also observed with increased frequency among fetuses who are homozygous for thalassemia. Drugs that block the potassium current, whether as the prime site of action or as a side effect, are highly teratogenic in experimental animals. They induce embryonic bradycardia, hypoxia, hemorrhage, and blisters, leading to transverse limb defects as well as craniofacial and cardiovascular defects. While evidence linking these drugs to birth defects in humans is not compelling, the reason may methodological rather than biological. Birth Defects Research 109:1358-1376, 2017.© 2017 Wiley Periodicals, Inc.

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Disruption of spatiotemporal hypoxic signaling causes congenital heart disease in mice

Cited by 37 publications

References 60 publications

Single cell RNA-seq and ATAC-seq indicate critical roles of Isl1 and Nkx2-5 for cardiac progenitor cell transition states and lineage settlement

Single cell RNA-seq and ATAC-seq indicate critical roles of Isl1 and Nkx2-5 for cardiac progenitor cell transition states and lineage settlement

Metabolic reprogramming from glycolysis to amino acid utilization in cardiac HIF1α deficient mice

Early Gestational Hypoxia and Adverse Developmental Outcomes

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