Background: The cardiac regenerative potential of newly developed therapies is traditionally eval... more Background: The cardiac regenerative potential of newly developed therapies is traditionally evaluated in rodent models of surgically induced myocardial ischemia. A generally accepted key parameter for determining the success of the applied therapy is the infarct size. Although regarded as a gold standard method for infarct size estimation in heart ischemia, histological planimetry is time-consuming and highly variable amongst studies. The purpose of this work is to contribute towards the standardization and simplification of infarct size assessment by providing free access to a novel semiautomated software tool. The acronym MIQuant was attributed to this application. Methodology/Principal Findings: Mice were subject to permanent coronary artery ligation and the size of chronic infarcts was estimated by area and midline-length methods using manual planimetry and with MIQuant. Repeatability and reproducibility of MIQuant scores were verified. The validation showed high correlation (r...
The epicardium is a reservoir of progenitors that give rise to coronary vasculature and stroma du... more The epicardium is a reservoir of progenitors that give rise to coronary vasculature and stroma during development and mediates cardiac vascular repair in lower vertebrates. However, its role as a source of progenitors in the adult mammalian heart remains unclear due to lack of clear lineage markers and single-cell culture systems to elucidate epicardial progeny cell fate. We found that in vivo exposure of mice to physiological hypoxia induced adult epicardial cells to re-enter the cell cycle and to express a subset of developmental genes. Multiplex transcriptional profiling revealed a lineage relationship between epicardial cells and smooth muscle, stromal, and endothelial fates, and that physiological hypoxia promoted an endothelial cell fate. In vitro analyses of purified epicardial cells showed that cell growth and subsequent differentiation is dependent upon hypoxia, and that resident epicardial cells retain progenitor identity in the adult mammalian heart with self-renewal and ...
Skeletal muscle injury results in a disruption of the muscle bed vascular network. A local source... more Skeletal muscle injury results in a disruption of the muscle bed vascular network. A local source of vascular progenitors during muscle regeneration has not been clearly identified. Fibroadipogenic progenitors (FAPs) are required for proper regeneration, however they can also directly contribute to fibrotic and fatty infiltration in response to chronic muscle injury and muscle disease. We show here that acute muscle injury leads to hypoxia and glucose deprivation, triggering FAP proliferation and differentiation into endothelial cells in vitro and in vivo. In response to glucose deprivation, FAPs down regulate fibrotic and fat associated genes and acquire an endothelial cell fate, which is dependent upon mTORC2-HIF2α-eNOS pathway. These findings bring new insights into the mechanisms of vascular regeneration during muscle regeneration and define a highly plastic resident progenitor population that responds to oxygen/glucose-deprivation induced cell stress by promoting an endothelial...
The establishment of separated pulmonary and systemic circulation in vertebrates, via cardiac out... more The establishment of separated pulmonary and systemic circulation in vertebrates, via cardiac outflow tract (OFT) septation, is a sensitive developmental process accounting for 10% of all congenital anomalies. Neural Crest Cells (NCC) colonising the heart condensate along the primitive endocardial tube and force its scission into two tubes. Here, we show that NCC aggregation progressively decreases along the OFT distal-proximal axis following a BMP signalling gradient. Dullard, a nuclear phosphatase, tunes the BMP gradient amplitude and prevents NCC premature condensation. Dullard maintains transcriptional programs providing NCC with mesenchymal traits. It attenuates the expression of the aggregation factor Sema3c and conversely promotes that of the epithelial-mesenchymal transition driver Twist1. Altogether, Dullard-mediated fine-tuning of BMP signalling ensures the timed and progressive zipper-like closure of the OFT by the NCC and prevents the formation of a heart carrying the co...
SummaryEstablishment of separated pulmonary and systemic circulations in vertebrates relies on th... more SummaryEstablishment of separated pulmonary and systemic circulations in vertebrates relies on the key role of neural crest cells (NCC) for the septation of the embryonic cardiac outflow tract (OFT). Absence of NCCs induces OFT septation defects, analogous to a loss of Bone Morphogenetic Proteins (BMPs) activity, though it remains unclear how BMPs control cardiac NCC differentiation and behaviour. To address this question, we monitored cardiac NCC state upon gain in BMP signaling, caused by the deletion of Dullard, using 3D-imaging and single cell transcriptomics. Specific loss of Dullard in the NCC results in premature OFT septation, pulmonary artery obstruction and embryonic death. This is caused by uncontrolled NCC convergence towards the endocardium and asymmetrical myocardial differentiation, promoted by elevated levels of the guiding cue Sema3c and decreased levels in mesenchymal trait markers. Furthermore, we unraveled the molecular basis of the zipper-like OFT septation wher...
The assessment of the regenerative capacity of the heart has been compromised by the lack of surf... more The assessment of the regenerative capacity of the heart has been compromised by the lack of surface signatures to characterize cardiomyocytes. Here, combined multiparametric surface marker analysis with single cell transcriptional profiling and in vivo transplantation, identify the main fetal cardiac populations and their progenitors. We found that cardiomyocytes at different stages of differentiation co-exist during development. We identified a population of immature HSA/CD24+ cardiomyocytes that persists throughout life and that, unlike other cardiomyocyte subsets, actively proliferates up to one week of age and engraft cardiac tissue upon transplantation. In adult heart HSA/CD24+ cardiomyocytes appear as mononucleated cells that cycle and increase in frequency after infarction. Our work identified cell surface signatures that allow the prospective isolation of cardiomyocytes at any developmental stage and the detection of adult cardiomyocytes poised for activation in response to...
Background: The cardiac regenerative potential of newly developed therapies is traditionally eval... more Background: The cardiac regenerative potential of newly developed therapies is traditionally evaluated in rodent models of surgically induced myocardial ischemia. A generally accepted key parameter for determining the success of the applied therapy is the infarct size. Although regarded as a gold standard method for infarct size estimation in heart ischemia, histological planimetry is time-consuming and highly variable amongst studies. The purpose of this work is to contribute towards the standardization and simplification of infarct size assessment by providing free access to a novel semiautomated software tool. The acronym MIQuant was attributed to this application. Methodology/Principal Findings: Mice were subject to permanent coronary artery ligation and the size of chronic infarcts was estimated by area and midline-length methods using manual planimetry and with MIQuant. Repeatability and reproducibility of MIQuant scores were verified. The validation showed high correlation (r...
The epicardium is a reservoir of progenitors that give rise to coronary vasculature and stroma du... more The epicardium is a reservoir of progenitors that give rise to coronary vasculature and stroma during development and mediates cardiac vascular repair in lower vertebrates. However, its role as a source of progenitors in the adult mammalian heart remains unclear due to lack of clear lineage markers and single-cell culture systems to elucidate epicardial progeny cell fate. We found that in vivo exposure of mice to physiological hypoxia induced adult epicardial cells to re-enter the cell cycle and to express a subset of developmental genes. Multiplex transcriptional profiling revealed a lineage relationship between epicardial cells and smooth muscle, stromal, and endothelial fates, and that physiological hypoxia promoted an endothelial cell fate. In vitro analyses of purified epicardial cells showed that cell growth and subsequent differentiation is dependent upon hypoxia, and that resident epicardial cells retain progenitor identity in the adult mammalian heart with self-renewal and ...
Skeletal muscle injury results in a disruption of the muscle bed vascular network. A local source... more Skeletal muscle injury results in a disruption of the muscle bed vascular network. A local source of vascular progenitors during muscle regeneration has not been clearly identified. Fibroadipogenic progenitors (FAPs) are required for proper regeneration, however they can also directly contribute to fibrotic and fatty infiltration in response to chronic muscle injury and muscle disease. We show here that acute muscle injury leads to hypoxia and glucose deprivation, triggering FAP proliferation and differentiation into endothelial cells in vitro and in vivo. In response to glucose deprivation, FAPs down regulate fibrotic and fat associated genes and acquire an endothelial cell fate, which is dependent upon mTORC2-HIF2α-eNOS pathway. These findings bring new insights into the mechanisms of vascular regeneration during muscle regeneration and define a highly plastic resident progenitor population that responds to oxygen/glucose-deprivation induced cell stress by promoting an endothelial...
The establishment of separated pulmonary and systemic circulation in vertebrates, via cardiac out... more The establishment of separated pulmonary and systemic circulation in vertebrates, via cardiac outflow tract (OFT) septation, is a sensitive developmental process accounting for 10% of all congenital anomalies. Neural Crest Cells (NCC) colonising the heart condensate along the primitive endocardial tube and force its scission into two tubes. Here, we show that NCC aggregation progressively decreases along the OFT distal-proximal axis following a BMP signalling gradient. Dullard, a nuclear phosphatase, tunes the BMP gradient amplitude and prevents NCC premature condensation. Dullard maintains transcriptional programs providing NCC with mesenchymal traits. It attenuates the expression of the aggregation factor Sema3c and conversely promotes that of the epithelial-mesenchymal transition driver Twist1. Altogether, Dullard-mediated fine-tuning of BMP signalling ensures the timed and progressive zipper-like closure of the OFT by the NCC and prevents the formation of a heart carrying the co...
SummaryEstablishment of separated pulmonary and systemic circulations in vertebrates relies on th... more SummaryEstablishment of separated pulmonary and systemic circulations in vertebrates relies on the key role of neural crest cells (NCC) for the septation of the embryonic cardiac outflow tract (OFT). Absence of NCCs induces OFT septation defects, analogous to a loss of Bone Morphogenetic Proteins (BMPs) activity, though it remains unclear how BMPs control cardiac NCC differentiation and behaviour. To address this question, we monitored cardiac NCC state upon gain in BMP signaling, caused by the deletion of Dullard, using 3D-imaging and single cell transcriptomics. Specific loss of Dullard in the NCC results in premature OFT septation, pulmonary artery obstruction and embryonic death. This is caused by uncontrolled NCC convergence towards the endocardium and asymmetrical myocardial differentiation, promoted by elevated levels of the guiding cue Sema3c and decreased levels in mesenchymal trait markers. Furthermore, we unraveled the molecular basis of the zipper-like OFT septation wher...
The assessment of the regenerative capacity of the heart has been compromised by the lack of surf... more The assessment of the regenerative capacity of the heart has been compromised by the lack of surface signatures to characterize cardiomyocytes. Here, combined multiparametric surface marker analysis with single cell transcriptional profiling and in vivo transplantation, identify the main fetal cardiac populations and their progenitors. We found that cardiomyocytes at different stages of differentiation co-exist during development. We identified a population of immature HSA/CD24+ cardiomyocytes that persists throughout life and that, unlike other cardiomyocyte subsets, actively proliferates up to one week of age and engraft cardiac tissue upon transplantation. In adult heart HSA/CD24+ cardiomyocytes appear as mononucleated cells that cycle and increase in frequency after infarction. Our work identified cell surface signatures that allow the prospective isolation of cardiomyocytes at any developmental stage and the detection of adult cardiomyocytes poised for activation in response to...
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