The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Shalini Muralidhar - One of the best experts on this subject based on the ideXlab platform.
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a calcineurin hoxb13 axis regulates growth mode of mammalian Cardiomyocytes
Nature, 2020Co-Authors: Ngoc Uyen Nhi Nguyen, Diana C Canseco, Yuji Nakada, Jainy Savla, Victor Le, Joseph A. Hill, Shalini Muralidhar, Feng Xiao, Shujuan Li, Kareem A ZidanAbstract:A major factor in the progression to heart failure in humans is the inability of the adult heart to repair itself after injury. We recently demonstrated that the early postnatal mammalian heart is capable of regeneration following injury through proliferation of preexisting Cardiomyocytes1,2 and that Meis1, a three amino acid loop extension (TALE) family homeodomain transcription factor, translocates to Cardiomyocyte nuclei shortly after birth and mediates postnatal cell cycle arrest3. Here we report that Hoxb13 acts as a cofactor of Meis1 in postnatal Cardiomyocytes. Cardiomyocyte-specific deletion of Hoxb13 can extend the postnatal window of Cardiomyocyte proliferation and reactivate the Cardiomyocyte cell cycle in the adult heart. Moreover, adult Meis1–Hoxb13 double-knockout hearts display widespread Cardiomyocyte mitosis, sarcomere disassembly and improved left ventricular systolic function following myocardial infarction, as demonstrated by echocardiography and magnetic resonance imaging. Chromatin immunoprecipitation with sequencing demonstrates that Meis1 and Hoxb13 act cooperatively to regulate Cardiomyocyte maturation and cell cycle. Finally, we show that the calcium-activated protein phosphatase calcineurin dephosphorylates Hoxb13 at serine-204, resulting in its nuclear localization and cell cycle arrest. These results demonstrate that Meis1 and Hoxb13 act cooperatively to regulate Cardiomyocyte maturation and proliferation and provide mechanistic insights into the link between hyperplastic and hypertrophic growth of Cardiomyocytes. Hoxb13 acts as a cofactor of Meis1 in regulating Cardiomyocyte maturation and cell cycle, and knockout of both proteins enables regeneration of postnatal cardiac tissue in a mouse model of heart injury.
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a calcineurin hoxb13 axis regulates growth mode of mammalian Cardiomyocytes
Nature, 2020Co-Authors: Ngoc Uyen Nhi Nguyen, Diana C Canseco, Yuji Nakada, Jainy Savla, Kareem A Zidan, Joseph A. Hill, Shalini Muralidhar, Feng Xiao, Nicholas T Lam, Hamed W ElfekyAbstract:A major factor in the progression to heart failure in humans is the inability of the adult heart to repair itself after injury. We recently demonstrated that the early postnatal mammalian heart is capable of regeneration following injury through proliferation of preexisting Cardiomyocytes1,2 and that Meis1, a three amino acid loop extension (TALE) family homeodomain transcription factor, translocates to Cardiomyocyte nuclei shortly after birth and mediates postnatal cell cycle arrest3. Here we report that Hoxb13 acts as a cofactor of Meis1 in postnatal Cardiomyocytes. Cardiomyocyte-specific deletion of Hoxb13 can extend the postnatal window of Cardiomyocyte proliferation and reactivate the Cardiomyocyte cell cycle in the adult heart. Moreover, adult Meis1-Hoxb13 double-knockout hearts display widespread Cardiomyocyte mitosis, sarcomere disassembly and improved left ventricular systolic function following myocardial infarction, as demonstrated by echocardiography and magnetic resonance imaging. Chromatin immunoprecipitation with sequencing demonstrates that Meis1 and Hoxb13 act cooperatively to regulate Cardiomyocyte maturation and cell cycle. Finally, we show that the calcium-activated protein phosphatase calcineurin dephosphorylates Hoxb13 at serine-204, resulting in its nuclear localization and cell cycle arrest. These results demonstrate that Meis1 and Hoxb13 act cooperatively to regulate Cardiomyocyte maturation and proliferation and provide mechanistic insights into the link between hyperplastic and hypertrophic growth of Cardiomyocytes.
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hypoxia fate mapping identifies cycling Cardiomyocytes in the adult heart
Nature, 2015Co-Authors: Diana C Canseco, Shalini Muralidhar, Feng Xiao, Wataru Kimura, Suwannee Thet, Helen M Zhang, Yezan Abderrahman, Rui Chen, Joseph A GarciaAbstract:Fate-mapping hypoxic cells in the mouse heart identifies a rare population of cycling Cardiomyocytes, which show characteristics of neonatal Cardiomyocytes, including smaller size and mononucleation, and contribute to new Cardiomyocyte formation in the adult heart. It was shown recently that new Cardiomyocytes in the adult heart are derived from pre-existing Cardiomyocytes, but their ultimate origin is not known. Hesham Sadek and colleagues have developed a strategy to fate-map hypoxic cells and demonstrate its use in the mouse heart to identify a rare population of cycling Cardiomyocytes. These cells show characteristics of neonatal Cardiomyocytes, including smaller size and mononucleation and they contribute widely to new Cardiomyocyte formation in the adult heart. Hypoxia signalling is emerging as a critical factor in the maintenance of proliferative competency of numerous stem cell and progenitor populations. Although the adult mammalian heart is incapable of meaningful functional recovery following substantial Cardiomyocyte loss, it is now clear that modest Cardiomyocyte turnover occurs in adult mouse and human hearts1,2, mediated primarily by proliferation of pre-existing Cardiomyocytes3,4,5. However, fate mapping of these cycling Cardiomyocytes has not been possible thus far owing to the lack of identifiable genetic markers6. In several organs, stem or progenitor cells reside in relatively hypoxic microenvironments where the stabilization of the hypoxia-inducible factor 1 alpha (Hif-1α) subunit is critical for their maintenance and function7,8,9,10. Here we report fate mapping of hypoxic cells and their progenies by generating a transgenic mouse expressing a chimaeric protein in which the oxygen-dependent degradation (ODD) domain of Hif-1α is fused to the tamoxifen-inducible CreERT2 recombinase. In mice bearing the creERT2-ODD transgene driven by either the ubiquitous CAG promoter or the Cardiomyocyte-specific α myosin heavy chain promoter, we identify a rare population of hypoxic Cardiomyocytes that display characteristics of proliferative neonatal Cardiomyocytes, such as smaller size, mononucleation and lower oxidative DNA damage. Notably, these hypoxic Cardiomyocytes contributed widely to new Cardiomyocyte formation in the adult heart. These results indicate that hypoxia signalling is an important hallmark of cycling Cardiomyocytes, and suggest that hypoxia fate mapping can be a powerful tool for identifying cycling cells in adult mammals.
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the oxygen rich postnatal environment induces Cardiomyocyte cell cycle arrest through dna damage response
Cell, 2014Co-Authors: Bao N Puente, Shalini Muralidhar, Wataru Kimura, Rui Chen, Jesung Moon, James F Amatruda, Katherine J Phelps, David Grinsfelder, Beverly A Rothermel, Joseph A GarciaAbstract:The mammalian heart has a remarkable regenerative capacity for a short period of time after birth, after which the majority of Cardiomyocytes permanently exit cell cycle. We sought to determine the primary postnatal event that results in Cardiomyocyte cell-cycle arrest. We hypothesized that transition to the oxygen-rich postnatal environment is the upstream signal that results in cell-cycle arrest of Cardiomyocytes. Here, we show that reactive oxygen species (ROS), oxidative DNA damage, and DNA damage response (DDR) markers significantly increase in the heart during the first postnatal week. Intriguingly, postnatal hypoxemia, ROS scavenging, or inhibition of DDR all prolong the postnatal proliferative window of Cardiomyocytes, whereas hyperoxemia and ROS generators shorten it. These findings uncover a protective mechanism that mediates Cardiomyocyte cell-cycle arrest in exchange for utilization of oxygen-dependent aerobic metabolism. Reduction of mitochondrial-dependent oxidative stress should be an important component of Cardiomyocyte proliferation-based therapeutic approaches.
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meis1 regulates postnatal Cardiomyocyte cell cycle arrest
Nature, 2013Co-Authors: Ahmed I Mahmoud, Shalini Muralidhar, Wataru Kimura, Suwannee Thet, Fatih Kocabas, Ahmed Salah Koura, Enzo R Porrello, Hesham A SadekAbstract:The neonatal mammalian heart is capable of substantial regeneration following injury through Cardiomyocyte proliferation (Porrello et al, Science 331:1078–1080, 2011; Proc Natl Acad Sci U S A 110:187–92, 2013). However, this regenerative capacity is lost by postnatal day 7 and the mechanisms of Cardiomyocyte cell cycle arrest remain unclear. The homeodomain transcription factor Meis1 is required for normal cardiac development but its role in Cardiomyocytes is unknown (Paige et al, Cell 151:221–232, 2012; Wamstad et al, Cell 151: 206–220, 2012). Here we identify Meis1 as a critical regulator of the Cardiomyocyte cell cycle. Meis1 deletion in mouse Cardiomyocytes was sufficient for extension of the postnatal proliferative window of Cardiomyocytes and for reactivation of Cardiomyocyte mitosis in the adult heart with no deleterious effect on cardiac function. In contrast, overexpression of Meis1 in Cardiomyocytes decreased neonatal myocyte proliferation and inhibited neonatal heart regeneration. Finally, we show that Meis1 is required for transcriptional activation of the synergistic CDK inhibitors p15, p16, and p21. These results identify Meis1 as a critical transcriptional regulator of Cardiomyocyte proliferation and a potential therapeutic target for heart regeneration.
Kareem A Zidan - One of the best experts on this subject based on the ideXlab platform.
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a calcineurin hoxb13 axis regulates growth mode of mammalian Cardiomyocytes
Nature, 2020Co-Authors: Ngoc Uyen Nhi Nguyen, Diana C Canseco, Yuji Nakada, Jainy Savla, Victor Le, Joseph A. Hill, Shalini Muralidhar, Feng Xiao, Shujuan Li, Kareem A ZidanAbstract:A major factor in the progression to heart failure in humans is the inability of the adult heart to repair itself after injury. We recently demonstrated that the early postnatal mammalian heart is capable of regeneration following injury through proliferation of preexisting Cardiomyocytes1,2 and that Meis1, a three amino acid loop extension (TALE) family homeodomain transcription factor, translocates to Cardiomyocyte nuclei shortly after birth and mediates postnatal cell cycle arrest3. Here we report that Hoxb13 acts as a cofactor of Meis1 in postnatal Cardiomyocytes. Cardiomyocyte-specific deletion of Hoxb13 can extend the postnatal window of Cardiomyocyte proliferation and reactivate the Cardiomyocyte cell cycle in the adult heart. Moreover, adult Meis1–Hoxb13 double-knockout hearts display widespread Cardiomyocyte mitosis, sarcomere disassembly and improved left ventricular systolic function following myocardial infarction, as demonstrated by echocardiography and magnetic resonance imaging. Chromatin immunoprecipitation with sequencing demonstrates that Meis1 and Hoxb13 act cooperatively to regulate Cardiomyocyte maturation and cell cycle. Finally, we show that the calcium-activated protein phosphatase calcineurin dephosphorylates Hoxb13 at serine-204, resulting in its nuclear localization and cell cycle arrest. These results demonstrate that Meis1 and Hoxb13 act cooperatively to regulate Cardiomyocyte maturation and proliferation and provide mechanistic insights into the link between hyperplastic and hypertrophic growth of Cardiomyocytes. Hoxb13 acts as a cofactor of Meis1 in regulating Cardiomyocyte maturation and cell cycle, and knockout of both proteins enables regeneration of postnatal cardiac tissue in a mouse model of heart injury.
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a calcineurin hoxb13 axis regulates growth mode of mammalian Cardiomyocytes
Nature, 2020Co-Authors: Ngoc Uyen Nhi Nguyen, Diana C Canseco, Yuji Nakada, Jainy Savla, Kareem A Zidan, Joseph A. Hill, Shalini Muralidhar, Feng Xiao, Nicholas T Lam, Hamed W ElfekyAbstract:A major factor in the progression to heart failure in humans is the inability of the adult heart to repair itself after injury. We recently demonstrated that the early postnatal mammalian heart is capable of regeneration following injury through proliferation of preexisting Cardiomyocytes1,2 and that Meis1, a three amino acid loop extension (TALE) family homeodomain transcription factor, translocates to Cardiomyocyte nuclei shortly after birth and mediates postnatal cell cycle arrest3. Here we report that Hoxb13 acts as a cofactor of Meis1 in postnatal Cardiomyocytes. Cardiomyocyte-specific deletion of Hoxb13 can extend the postnatal window of Cardiomyocyte proliferation and reactivate the Cardiomyocyte cell cycle in the adult heart. Moreover, adult Meis1-Hoxb13 double-knockout hearts display widespread Cardiomyocyte mitosis, sarcomere disassembly and improved left ventricular systolic function following myocardial infarction, as demonstrated by echocardiography and magnetic resonance imaging. Chromatin immunoprecipitation with sequencing demonstrates that Meis1 and Hoxb13 act cooperatively to regulate Cardiomyocyte maturation and cell cycle. Finally, we show that the calcium-activated protein phosphatase calcineurin dephosphorylates Hoxb13 at serine-204, resulting in its nuclear localization and cell cycle arrest. These results demonstrate that Meis1 and Hoxb13 act cooperatively to regulate Cardiomyocyte maturation and proliferation and provide mechanistic insights into the link between hyperplastic and hypertrophic growth of Cardiomyocytes.
Ngoc Uyen Nhi Nguyen - One of the best experts on this subject based on the ideXlab platform.
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a calcineurin hoxb13 axis regulates growth mode of mammalian Cardiomyocytes
Nature, 2020Co-Authors: Ngoc Uyen Nhi Nguyen, Diana C Canseco, Yuji Nakada, Jainy Savla, Victor Le, Joseph A. Hill, Shalini Muralidhar, Feng Xiao, Shujuan Li, Kareem A ZidanAbstract:A major factor in the progression to heart failure in humans is the inability of the adult heart to repair itself after injury. We recently demonstrated that the early postnatal mammalian heart is capable of regeneration following injury through proliferation of preexisting Cardiomyocytes1,2 and that Meis1, a three amino acid loop extension (TALE) family homeodomain transcription factor, translocates to Cardiomyocyte nuclei shortly after birth and mediates postnatal cell cycle arrest3. Here we report that Hoxb13 acts as a cofactor of Meis1 in postnatal Cardiomyocytes. Cardiomyocyte-specific deletion of Hoxb13 can extend the postnatal window of Cardiomyocyte proliferation and reactivate the Cardiomyocyte cell cycle in the adult heart. Moreover, adult Meis1–Hoxb13 double-knockout hearts display widespread Cardiomyocyte mitosis, sarcomere disassembly and improved left ventricular systolic function following myocardial infarction, as demonstrated by echocardiography and magnetic resonance imaging. Chromatin immunoprecipitation with sequencing demonstrates that Meis1 and Hoxb13 act cooperatively to regulate Cardiomyocyte maturation and cell cycle. Finally, we show that the calcium-activated protein phosphatase calcineurin dephosphorylates Hoxb13 at serine-204, resulting in its nuclear localization and cell cycle arrest. These results demonstrate that Meis1 and Hoxb13 act cooperatively to regulate Cardiomyocyte maturation and proliferation and provide mechanistic insights into the link between hyperplastic and hypertrophic growth of Cardiomyocytes. Hoxb13 acts as a cofactor of Meis1 in regulating Cardiomyocyte maturation and cell cycle, and knockout of both proteins enables regeneration of postnatal cardiac tissue in a mouse model of heart injury.
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a calcineurin hoxb13 axis regulates growth mode of mammalian Cardiomyocytes
Nature, 2020Co-Authors: Ngoc Uyen Nhi Nguyen, Diana C Canseco, Yuji Nakada, Jainy Savla, Kareem A Zidan, Joseph A. Hill, Shalini Muralidhar, Feng Xiao, Nicholas T Lam, Hamed W ElfekyAbstract:A major factor in the progression to heart failure in humans is the inability of the adult heart to repair itself after injury. We recently demonstrated that the early postnatal mammalian heart is capable of regeneration following injury through proliferation of preexisting Cardiomyocytes1,2 and that Meis1, a three amino acid loop extension (TALE) family homeodomain transcription factor, translocates to Cardiomyocyte nuclei shortly after birth and mediates postnatal cell cycle arrest3. Here we report that Hoxb13 acts as a cofactor of Meis1 in postnatal Cardiomyocytes. Cardiomyocyte-specific deletion of Hoxb13 can extend the postnatal window of Cardiomyocyte proliferation and reactivate the Cardiomyocyte cell cycle in the adult heart. Moreover, adult Meis1-Hoxb13 double-knockout hearts display widespread Cardiomyocyte mitosis, sarcomere disassembly and improved left ventricular systolic function following myocardial infarction, as demonstrated by echocardiography and magnetic resonance imaging. Chromatin immunoprecipitation with sequencing demonstrates that Meis1 and Hoxb13 act cooperatively to regulate Cardiomyocyte maturation and cell cycle. Finally, we show that the calcium-activated protein phosphatase calcineurin dephosphorylates Hoxb13 at serine-204, resulting in its nuclear localization and cell cycle arrest. These results demonstrate that Meis1 and Hoxb13 act cooperatively to regulate Cardiomyocyte maturation and proliferation and provide mechanistic insights into the link between hyperplastic and hypertrophic growth of Cardiomyocytes.
Jainy Savla - One of the best experts on this subject based on the ideXlab platform.
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a calcineurin hoxb13 axis regulates growth mode of mammalian Cardiomyocytes
Nature, 2020Co-Authors: Ngoc Uyen Nhi Nguyen, Diana C Canseco, Yuji Nakada, Jainy Savla, Victor Le, Joseph A. Hill, Shalini Muralidhar, Feng Xiao, Shujuan Li, Kareem A ZidanAbstract:A major factor in the progression to heart failure in humans is the inability of the adult heart to repair itself after injury. We recently demonstrated that the early postnatal mammalian heart is capable of regeneration following injury through proliferation of preexisting Cardiomyocytes1,2 and that Meis1, a three amino acid loop extension (TALE) family homeodomain transcription factor, translocates to Cardiomyocyte nuclei shortly after birth and mediates postnatal cell cycle arrest3. Here we report that Hoxb13 acts as a cofactor of Meis1 in postnatal Cardiomyocytes. Cardiomyocyte-specific deletion of Hoxb13 can extend the postnatal window of Cardiomyocyte proliferation and reactivate the Cardiomyocyte cell cycle in the adult heart. Moreover, adult Meis1–Hoxb13 double-knockout hearts display widespread Cardiomyocyte mitosis, sarcomere disassembly and improved left ventricular systolic function following myocardial infarction, as demonstrated by echocardiography and magnetic resonance imaging. Chromatin immunoprecipitation with sequencing demonstrates that Meis1 and Hoxb13 act cooperatively to regulate Cardiomyocyte maturation and cell cycle. Finally, we show that the calcium-activated protein phosphatase calcineurin dephosphorylates Hoxb13 at serine-204, resulting in its nuclear localization and cell cycle arrest. These results demonstrate that Meis1 and Hoxb13 act cooperatively to regulate Cardiomyocyte maturation and proliferation and provide mechanistic insights into the link between hyperplastic and hypertrophic growth of Cardiomyocytes. Hoxb13 acts as a cofactor of Meis1 in regulating Cardiomyocyte maturation and cell cycle, and knockout of both proteins enables regeneration of postnatal cardiac tissue in a mouse model of heart injury.
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a calcineurin hoxb13 axis regulates growth mode of mammalian Cardiomyocytes
Nature, 2020Co-Authors: Ngoc Uyen Nhi Nguyen, Diana C Canseco, Yuji Nakada, Jainy Savla, Kareem A Zidan, Joseph A. Hill, Shalini Muralidhar, Feng Xiao, Nicholas T Lam, Hamed W ElfekyAbstract:A major factor in the progression to heart failure in humans is the inability of the adult heart to repair itself after injury. We recently demonstrated that the early postnatal mammalian heart is capable of regeneration following injury through proliferation of preexisting Cardiomyocytes1,2 and that Meis1, a three amino acid loop extension (TALE) family homeodomain transcription factor, translocates to Cardiomyocyte nuclei shortly after birth and mediates postnatal cell cycle arrest3. Here we report that Hoxb13 acts as a cofactor of Meis1 in postnatal Cardiomyocytes. Cardiomyocyte-specific deletion of Hoxb13 can extend the postnatal window of Cardiomyocyte proliferation and reactivate the Cardiomyocyte cell cycle in the adult heart. Moreover, adult Meis1-Hoxb13 double-knockout hearts display widespread Cardiomyocyte mitosis, sarcomere disassembly and improved left ventricular systolic function following myocardial infarction, as demonstrated by echocardiography and magnetic resonance imaging. Chromatin immunoprecipitation with sequencing demonstrates that Meis1 and Hoxb13 act cooperatively to regulate Cardiomyocyte maturation and cell cycle. Finally, we show that the calcium-activated protein phosphatase calcineurin dephosphorylates Hoxb13 at serine-204, resulting in its nuclear localization and cell cycle arrest. These results demonstrate that Meis1 and Hoxb13 act cooperatively to regulate Cardiomyocyte maturation and proliferation and provide mechanistic insights into the link between hyperplastic and hypertrophic growth of Cardiomyocytes.
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mitochondrial substrate utilization regulates Cardiomyocyte cell cycle progression
Nature Metabolism, 2020Co-Authors: Alisson C Cardoso, Yuji Nakada, Jainy Savla, Ana Helena M Pereira, Abdallah Elnwasany, Ivan Menendezmontes, Emily L Ensley, Ursa Bezan Petric, Gaurav Sharma, Dean A SherryAbstract: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 postnatal 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. Proliferation of Cardiomyocytes typically ceases shortly after birth. Here the authors show that decreasing fatty-acid oxidation extends the perinatal Cardiomyocyte proliferative window and can reintroduce cell-cycle activity in adult Cardiomyocytes.
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Cardiomyocyte proliferation contributes to heart growth in young humans
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Mariya Mollova, Jainy Savla, Kevin R Bersell, Stuart Walsh, Lala Tanmoy Das, Shinyoung Park, Leslie E Silberstein, Cristobal Dos G Remedios, Dionne A GrahamAbstract:The human heart is believed to grow by enlargement but not proliferation of Cardiomyocytes (heart muscle cells) during postnatal development. However, recent studies have shown that Cardiomyocyte proliferation is a mechanism of cardiac growth and regeneration in animals. Combined with evidence for Cardiomyocyte turnover in adult humans, this suggests that Cardiomyocyte proliferation may play an unrecognized role during the period of developmental heart growth between birth and adolescence. We tested this hypothesis by examining the cellular growth mechanisms of the left ventricle on a set of healthy hearts from humans aged 0–59 y (n = 36). The percentages of Cardiomyocytes in mitosis and cytokinesis were highest in infants, decreasing to low levels by 20 y. Although Cardiomyocyte mitosis was detectable throughout life, Cardiomyocyte cytokinesis was not evident after 20 y. Between the first year and 20 y of life, the number of Cardiomyocytes in the left ventricle increased 3.4-fold, which was consistent with our predictions based on measured Cardiomyocyte cell cycle activity. Our findings show that Cardiomyocyte proliferation contributes to developmental heart growth in young humans. This suggests that children and adolescents may be able to regenerate myocardium, that abnormal Cardiomyocyte proliferation may be involved in myocardial diseases that affect this population, and that these diseases might be treatable through stimulation of Cardiomyocyte proliferation.
Diana C Canseco - One of the best experts on this subject based on the ideXlab platform.
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a calcineurin hoxb13 axis regulates growth mode of mammalian Cardiomyocytes
Nature, 2020Co-Authors: Ngoc Uyen Nhi Nguyen, Diana C Canseco, Yuji Nakada, Jainy Savla, Victor Le, Joseph A. Hill, Shalini Muralidhar, Feng Xiao, Shujuan Li, Kareem A ZidanAbstract:A major factor in the progression to heart failure in humans is the inability of the adult heart to repair itself after injury. We recently demonstrated that the early postnatal mammalian heart is capable of regeneration following injury through proliferation of preexisting Cardiomyocytes1,2 and that Meis1, a three amino acid loop extension (TALE) family homeodomain transcription factor, translocates to Cardiomyocyte nuclei shortly after birth and mediates postnatal cell cycle arrest3. Here we report that Hoxb13 acts as a cofactor of Meis1 in postnatal Cardiomyocytes. Cardiomyocyte-specific deletion of Hoxb13 can extend the postnatal window of Cardiomyocyte proliferation and reactivate the Cardiomyocyte cell cycle in the adult heart. Moreover, adult Meis1–Hoxb13 double-knockout hearts display widespread Cardiomyocyte mitosis, sarcomere disassembly and improved left ventricular systolic function following myocardial infarction, as demonstrated by echocardiography and magnetic resonance imaging. Chromatin immunoprecipitation with sequencing demonstrates that Meis1 and Hoxb13 act cooperatively to regulate Cardiomyocyte maturation and cell cycle. Finally, we show that the calcium-activated protein phosphatase calcineurin dephosphorylates Hoxb13 at serine-204, resulting in its nuclear localization and cell cycle arrest. These results demonstrate that Meis1 and Hoxb13 act cooperatively to regulate Cardiomyocyte maturation and proliferation and provide mechanistic insights into the link between hyperplastic and hypertrophic growth of Cardiomyocytes. Hoxb13 acts as a cofactor of Meis1 in regulating Cardiomyocyte maturation and cell cycle, and knockout of both proteins enables regeneration of postnatal cardiac tissue in a mouse model of heart injury.
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a calcineurin hoxb13 axis regulates growth mode of mammalian Cardiomyocytes
Nature, 2020Co-Authors: Ngoc Uyen Nhi Nguyen, Diana C Canseco, Yuji Nakada, Jainy Savla, Kareem A Zidan, Joseph A. Hill, Shalini Muralidhar, Feng Xiao, Nicholas T Lam, Hamed W ElfekyAbstract:A major factor in the progression to heart failure in humans is the inability of the adult heart to repair itself after injury. We recently demonstrated that the early postnatal mammalian heart is capable of regeneration following injury through proliferation of preexisting Cardiomyocytes1,2 and that Meis1, a three amino acid loop extension (TALE) family homeodomain transcription factor, translocates to Cardiomyocyte nuclei shortly after birth and mediates postnatal cell cycle arrest3. Here we report that Hoxb13 acts as a cofactor of Meis1 in postnatal Cardiomyocytes. Cardiomyocyte-specific deletion of Hoxb13 can extend the postnatal window of Cardiomyocyte proliferation and reactivate the Cardiomyocyte cell cycle in the adult heart. Moreover, adult Meis1-Hoxb13 double-knockout hearts display widespread Cardiomyocyte mitosis, sarcomere disassembly and improved left ventricular systolic function following myocardial infarction, as demonstrated by echocardiography and magnetic resonance imaging. Chromatin immunoprecipitation with sequencing demonstrates that Meis1 and Hoxb13 act cooperatively to regulate Cardiomyocyte maturation and cell cycle. Finally, we show that the calcium-activated protein phosphatase calcineurin dephosphorylates Hoxb13 at serine-204, resulting in its nuclear localization and cell cycle arrest. These results demonstrate that Meis1 and Hoxb13 act cooperatively to regulate Cardiomyocyte maturation and proliferation and provide mechanistic insights into the link between hyperplastic and hypertrophic growth of Cardiomyocytes.
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hypoxia fate mapping identifies cycling Cardiomyocytes in the adult heart
Nature, 2015Co-Authors: Diana C Canseco, Shalini Muralidhar, Feng Xiao, Wataru Kimura, Suwannee Thet, Helen M Zhang, Yezan Abderrahman, Rui Chen, Joseph A GarciaAbstract:Fate-mapping hypoxic cells in the mouse heart identifies a rare population of cycling Cardiomyocytes, which show characteristics of neonatal Cardiomyocytes, including smaller size and mononucleation, and contribute to new Cardiomyocyte formation in the adult heart. It was shown recently that new Cardiomyocytes in the adult heart are derived from pre-existing Cardiomyocytes, but their ultimate origin is not known. Hesham Sadek and colleagues have developed a strategy to fate-map hypoxic cells and demonstrate its use in the mouse heart to identify a rare population of cycling Cardiomyocytes. These cells show characteristics of neonatal Cardiomyocytes, including smaller size and mononucleation and they contribute widely to new Cardiomyocyte formation in the adult heart. Hypoxia signalling is emerging as a critical factor in the maintenance of proliferative competency of numerous stem cell and progenitor populations. Although the adult mammalian heart is incapable of meaningful functional recovery following substantial Cardiomyocyte loss, it is now clear that modest Cardiomyocyte turnover occurs in adult mouse and human hearts1,2, mediated primarily by proliferation of pre-existing Cardiomyocytes3,4,5. However, fate mapping of these cycling Cardiomyocytes has not been possible thus far owing to the lack of identifiable genetic markers6. In several organs, stem or progenitor cells reside in relatively hypoxic microenvironments where the stabilization of the hypoxia-inducible factor 1 alpha (Hif-1α) subunit is critical for their maintenance and function7,8,9,10. Here we report fate mapping of hypoxic cells and their progenies by generating a transgenic mouse expressing a chimaeric protein in which the oxygen-dependent degradation (ODD) domain of Hif-1α is fused to the tamoxifen-inducible CreERT2 recombinase. In mice bearing the creERT2-ODD transgene driven by either the ubiquitous CAG promoter or the Cardiomyocyte-specific α myosin heavy chain promoter, we identify a rare population of hypoxic Cardiomyocytes that display characteristics of proliferative neonatal Cardiomyocytes, such as smaller size, mononucleation and lower oxidative DNA damage. Notably, these hypoxic Cardiomyocytes contributed widely to new Cardiomyocyte formation in the adult heart. These results indicate that hypoxia signalling is an important hallmark of cycling Cardiomyocytes, and suggest that hypoxia fate mapping can be a powerful tool for identifying cycling cells in adult mammals.