Direct Comparison of Mononucleated and Binucleated Cardiomyocytes Reveals Molecular Mechanisms Underlying Distinct Proliferative Competencies
Summary: The mammalian heart is incapable of regenerating a sufficient number of cardiomyocytes to ameliorate the loss of contractile muscle after acute myocardial injury. Several reports have demonstrated that mononucleated cardiomyocytes are more responsive than are binucleated cardiomyocytes to p...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2020-03-01
|
| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124720301959 |
| _version_ | 1818175022511947776 |
|---|---|
| author | Rebecca Windmueller John P. Leach Apoorva Babu Su Zhou Michael P. Morley Aoi Wakabayashi Nataliya B. Petrenko Patrick Viatour Edward E. Morrisey |
| author_facet | Rebecca Windmueller John P. Leach Apoorva Babu Su Zhou Michael P. Morley Aoi Wakabayashi Nataliya B. Petrenko Patrick Viatour Edward E. Morrisey |
| author_sort | Rebecca Windmueller |
| collection | DOAJ |
| description | Summary: The mammalian heart is incapable of regenerating a sufficient number of cardiomyocytes to ameliorate the loss of contractile muscle after acute myocardial injury. Several reports have demonstrated that mononucleated cardiomyocytes are more responsive than are binucleated cardiomyocytes to pro-proliferative stimuli. We have developed a strategy to isolate and characterize highly enriched populations of mononucleated and binucleated cardiomyocytes at various times of development. Our results suggest that an E2f/Rb transcriptional network is central to the divergence of these two populations and that remnants of the differences acquired during the neonatal period remain in adult cardiomyocytes. Moreover, inducing binucleation by genetically blocking the ability of cardiomyocytes to complete cytokinesis leads to a reduction in E2f target gene expression, directly linking the E2f pathway with nucleation. These data identify key molecular differences between mononucleated and binucleated mammalian cardiomyocytes that can be used to leverage cardiomyocyte proliferation for promoting injury repair in the heart. : Windmueller et al. develop a strategy to separate mononucleated and binucleated cardiomyocytes and examine transcriptional differences acquired as the two subsets diverge during the neonatal period. Binucleation is associated with silencing of proliferation genes and upregulation of maturation genes. Genetic loss of Ect2 links binucleation to the Rb/E2f pathway. Keywords: cardiac regeneration, mononucleated, binucleated, cardiomyocyte, proliferation, Rb, E2f, Ect2, heart, development |
| first_indexed | 2024-12-11T19:53:41Z |
| format | Article |
| id | doaj.art-4cc9d514ae934b469d3b2fc8c7e2809f |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-11T19:53:41Z |
| publishDate | 2020-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-4cc9d514ae934b469d3b2fc8c7e2809f2022-12-22T00:52:43ZengElsevierCell Reports2211-12472020-03-0130931053116.e4Direct Comparison of Mononucleated and Binucleated Cardiomyocytes Reveals Molecular Mechanisms Underlying Distinct Proliferative CompetenciesRebecca Windmueller0John P. Leach1Apoorva Babu2Su Zhou3Michael P. Morley4Aoi Wakabayashi5Nataliya B. Petrenko6Patrick Viatour7Edward E. Morrisey8Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn-CHOP Lung Biology Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn-CHOP Lung Biology Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAPenn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn-CHOP Lung Biology Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn-CHOP Lung Biology Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Corresponding authorSummary: The mammalian heart is incapable of regenerating a sufficient number of cardiomyocytes to ameliorate the loss of contractile muscle after acute myocardial injury. Several reports have demonstrated that mononucleated cardiomyocytes are more responsive than are binucleated cardiomyocytes to pro-proliferative stimuli. We have developed a strategy to isolate and characterize highly enriched populations of mononucleated and binucleated cardiomyocytes at various times of development. Our results suggest that an E2f/Rb transcriptional network is central to the divergence of these two populations and that remnants of the differences acquired during the neonatal period remain in adult cardiomyocytes. Moreover, inducing binucleation by genetically blocking the ability of cardiomyocytes to complete cytokinesis leads to a reduction in E2f target gene expression, directly linking the E2f pathway with nucleation. These data identify key molecular differences between mononucleated and binucleated mammalian cardiomyocytes that can be used to leverage cardiomyocyte proliferation for promoting injury repair in the heart. : Windmueller et al. develop a strategy to separate mononucleated and binucleated cardiomyocytes and examine transcriptional differences acquired as the two subsets diverge during the neonatal period. Binucleation is associated with silencing of proliferation genes and upregulation of maturation genes. Genetic loss of Ect2 links binucleation to the Rb/E2f pathway. Keywords: cardiac regeneration, mononucleated, binucleated, cardiomyocyte, proliferation, Rb, E2f, Ect2, heart, developmenthttp://www.sciencedirect.com/science/article/pii/S2211124720301959 |
| spellingShingle | Rebecca Windmueller John P. Leach Apoorva Babu Su Zhou Michael P. Morley Aoi Wakabayashi Nataliya B. Petrenko Patrick Viatour Edward E. Morrisey Direct Comparison of Mononucleated and Binucleated Cardiomyocytes Reveals Molecular Mechanisms Underlying Distinct Proliferative Competencies Cell Reports |
| title | Direct Comparison of Mononucleated and Binucleated Cardiomyocytes Reveals Molecular Mechanisms Underlying Distinct Proliferative Competencies |
| title_full | Direct Comparison of Mononucleated and Binucleated Cardiomyocytes Reveals Molecular Mechanisms Underlying Distinct Proliferative Competencies |
| title_fullStr | Direct Comparison of Mononucleated and Binucleated Cardiomyocytes Reveals Molecular Mechanisms Underlying Distinct Proliferative Competencies |
| title_full_unstemmed | Direct Comparison of Mononucleated and Binucleated Cardiomyocytes Reveals Molecular Mechanisms Underlying Distinct Proliferative Competencies |
| title_short | Direct Comparison of Mononucleated and Binucleated Cardiomyocytes Reveals Molecular Mechanisms Underlying Distinct Proliferative Competencies |
| title_sort | direct comparison of mononucleated and binucleated cardiomyocytes reveals molecular mechanisms underlying distinct proliferative competencies |
| url | http://www.sciencedirect.com/science/article/pii/S2211124720301959 |
| work_keys_str_mv | AT rebeccawindmueller directcomparisonofmononucleatedandbinucleatedcardiomyocytesrevealsmolecularmechanismsunderlyingdistinctproliferativecompetencies AT johnpleach directcomparisonofmononucleatedandbinucleatedcardiomyocytesrevealsmolecularmechanismsunderlyingdistinctproliferativecompetencies AT apoorvababu directcomparisonofmononucleatedandbinucleatedcardiomyocytesrevealsmolecularmechanismsunderlyingdistinctproliferativecompetencies AT suzhou directcomparisonofmononucleatedandbinucleatedcardiomyocytesrevealsmolecularmechanismsunderlyingdistinctproliferativecompetencies AT michaelpmorley directcomparisonofmononucleatedandbinucleatedcardiomyocytesrevealsmolecularmechanismsunderlyingdistinctproliferativecompetencies AT aoiwakabayashi directcomparisonofmononucleatedandbinucleatedcardiomyocytesrevealsmolecularmechanismsunderlyingdistinctproliferativecompetencies AT nataliyabpetrenko directcomparisonofmononucleatedandbinucleatedcardiomyocytesrevealsmolecularmechanismsunderlyingdistinctproliferativecompetencies AT patrickviatour directcomparisonofmononucleatedandbinucleatedcardiomyocytesrevealsmolecularmechanismsunderlyingdistinctproliferativecompetencies AT edwardemorrisey directcomparisonofmononucleatedandbinucleatedcardiomyocytesrevealsmolecularmechanismsunderlyingdistinctproliferativecompetencies |