C-Kit Cells Do Not Significantly Contribute to Cardiomyogenesis During Neonatal Heart Regeneration

Elhelaly, Waleed M.; Cardoso, Alisson C.; Pereira, Ana Helena Macedo; Elnawasany, Abdallah; Ebrahimi, Shayda; Nakada, Yuji; Sadek, Hesham A.

doi:10.1161/circulationaha.117.033150

Cited by 20 publications

(14 citation statements)

References 6 publications

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“…One of the noteworthy attempts at finding a bona fide cardiac stem cell focused on resident cardiac C-kit+ cells. Although initial studies suggested a multipotent ability for these cells (Beltrami et al, 2003), lineage-tracing studies later indicated that these cells have negligible cardiomyogenic potential and instead seem to be primarily endothelial cell progenitors (Elhelaly et al, 2019;Sultana et al, 2015;van Berlo et al, 2014). The question of whether or not any nonmyocyte populations (including C-kit cells) contribute to cardiomyocyte generation in the adult heart has been recently investigated using the same dual recombinase fate-mapping strategy outlined above to demonstrate conclusively that non-myocytes do not contribute to cardiomyocyte generation in the adult heart, either under homeostatic conditions or after injury (Li et al, 2018).…”

Section: Non-cardiac Models Of Spontaneous Regenerationmentioning

confidence: 99%

Toward the Goal of Human Heart Regeneration

2020

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Heart regeneration, a relatively new field of biology, is one of the most active and controversial areas of biomedical research. The potential impact of successful human heart regeneration therapeutics cannot be overstated, given the magnitude and prognosis of heart failure. However, the regenerative process is highly complex, and premature claims of successful heart regeneration have both fueled interest and created controversy. The field as a whole is now in the process of course correction, and a clearer picture is beginning to emerge. Despite the challenges, fundamental principles in developmental biology have provided a framework for hypothesisdriven approaches toward the ultimate goal of adult heart regeneration and repair. In this review, we discuss the current state of the field and outline the potential paths forward toward regenerating the human myocardium.

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Section: Non-cardiac Models Of Spontaneous Regenerationmentioning

confidence: 99%

Toward the Goal of Human Heart Regeneration

2020

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“…Recent studies have demonstrated that removal of up to 15% of the left ventricular apex of postnatal day 1 (P1) mice results in regeneration by P21 3 , 24 . This regenerative response is mediated by proliferation of preexisting cardiomyocytes and is lost when cardiomyocytes permanently exit the cell cycle shortly after birth 3 , 25 . Similar results were obtained using an ischemic myocardial infarction (MI) model in neonatal mice 26 and large animals 27 , 28 .…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial substrate utilization regulates cardiomyocyte cell-cycle progression

et al. 2020

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The neonatal mammalian heart is capable of regeneration for a brief window of time after birth. However, this regenerative capacity is lost within the first week of life, which coincides with a postnatal shift from anaerobic glycolysis to mitochondrial oxidative phosphorylation, particularly towards fatty-acid utilization. Despite the energy advantage of fatty-acid beta-oxidation, cardiac mitochondria produce elevated rates of reactive oxygen species when utilizing fatty acids, which is thought to play a role in cardiomyocyte cell-cycle arrest through induction of DNA damage and activation of DNA-damage response (DDR) pathway. Here we show that inhibiting fatty-acid utilization promotes cardiomyocyte proliferation in the postnatatal heart. First, neonatal mice fed fatty-acid deficient milk showed prolongation of the postnatal cardiomyocyte proliferative window, however cell cycle arrest eventually ensued. Next, we generated a tamoxifen-inducible cardiomyocyte-specific, pyruvate dehydrogenase kinase 4 (PDK4) knockout mouse model to selectively enhance oxidation of glycolytically derived pyruvate in cardiomyocytes. Conditional PDK4 deletion resulted in an increase in pyruvate dehydrogenase activity and consequently an increase in glucose relative to fatty-acid oxidation. Loss of PDK4 also resulted in decreased cardiomyocyte size, decreased DNA damage and expression of DDR markers and an increase in cardiomyocyte proliferation. Following myocardial infarction, inducible deletion of PDK4 improved left ventricular function and decreased remodelling. Collectively, inhibition of fatty-acid utilization in cardiomyocytes promotes proliferation, and may be a viable target for cardiac regenerative therapies.

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“…Furthermore, the same group has shown that early segregation of myocytes and nonmyocytes during embryonic development (E10.5 to E11.5) is the cut-off line beyond which no contribution to new cardiomyocyte formation occurs, even during neonatal life [67]. Moreover, a study published earlier this year by Elhelaly and colleagues argued that c-kit-positive cells do not contribute to cardiomyogenesis, even during neonatal life [68]. Howbeit, the commonly agreed-upon consensus in the field is that CPCs are remnant SCs from developmental stages whose role in the adult heart, if any, confines to maintaining cardiac tissue homeostasis, and their cardiomyogenic potential in the context of injury is inexistent [69,70].…”

Section: Cardiac Progenitor Cells and Stem Cell Nichesmentioning

confidence: 99%

Stem Cells in Cardiovascular Medicine: Historical Overview and Future Prospects

Samak

Hinkel

2019

Cells

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Cardiovascular diseases remain the leading cause of death in the developed world, accounting for more than 30% of all deaths. In a large proportion of these patients, acute myocardial infarction is usually the first manifestation, which might further progress to heart failure. In addition, the human heart displays a low regenerative capacity, leading to a loss of cardiomyocytes and persistent tissue scaring, which entails a morbid pathologic sequela. Novel therapeutic approaches are urgently needed. Stem cells, such as induced pluripotent stem cells or embryonic stem cells, exhibit great potential for cell-replacement therapy and an excellent tool for disease modeling, as well as pharmaceutical screening of novel drugs and their cardiac side effects. This review article covers not only the origin of stem cells but tries to summarize their translational potential, as well as potential risks and clinical translation.

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C-Kit Cells Do Not Significantly Contribute to Cardiomyogenesis During Neonatal Heart Regeneration

Cited by 20 publications

References 6 publications

Toward the Goal of Human Heart Regeneration

Toward the Goal of Human Heart Regeneration

Mitochondrial substrate utilization regulates cardiomyocyte cell-cycle progression

Stem Cells in Cardiovascular Medicine: Historical Overview and Future Prospects

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