| 1. |
- Asp, Michaela, et al.
(author)
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A Spatiotemporal Organ-Wide Gene Expression and Cell Atlas of the Developing Human Heart
- 2019
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In: Cell. - : CELL PRESS. - 0092-8674 .- 1097-4172. ; 179:7, s. 1647-
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Journal article (peer-reviewed)abstract
- The process of cardiac morphogenesis in humans is incompletely understood. Its full characterization requires a deep exploration of the organ-wide orchestration of gene expression with a single-cell spatial resolution. Here, we present a molecular approach that reveals the comprehensive transcriptional landscape of cell types populating the embryonic heart at three developmental stages and that maps cell-type-specific gene expression to specific anatomical domains. Spatial transcriptomics identified unique gene profiles that correspond to distinct anatomical regions in each developmental stage. Human embryonic cardiac cell types identified by single-cell RNA sequencing confirmed and enriched the spatial annotation of embryonic cardiac gene expression. In situ sequencing was then used to refine these results and create a spatial subcellular map for the three developmental phases. Finally, we generated a publicly available web resource of the human developing heart to facilitate future studies on human cardiogenesis.
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| 2. |
- Baniol, Marion, et al.
(author)
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Identification and characterization of distinct cell cycle stages in cardiomyocytes using the FUCCI transgenic system
- 2021
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In: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 408:2
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Journal article (peer-reviewed)abstract
- Understanding the regulatory mechanism by which cardiomyocyte proliferation transitions to endoreplication and cell cycle arrest during the neonatal period is crucial for identifying proproliferative factors and developing regenerative therapies. We used a transgenic mouse model based on the fluorescent ubiquitination-based cell cycle indicator (FUCCI) system to isolate and characterize cycling cardiomyocytes at different cell cycle stages at a single-cell resolution. Single-cell transcriptome analysis of cycling and noncycling cardiomyocytes was performed at postnatal days 0 (P0) and 7 (P7). The FUCCI system proved to be efficient for the identification of cycling cardiomyocytes with the highest mitotic activity at birth, followed by a gradual decline in the number of cycling and mitotic cardiomyocytes during the neonatal period. Cardiomyocytes showed premature cell cycle exit at G1/S shortly after birth and delayed G1/S progression during endoreplication at P7. Single-cell RNA-seq confirmed previously described signaling pathways involved in cardiomyocyte proliferation (Erbb2 and Hippo/YAP), and maturation-related transcriptional changes during postnatal development, including the metabolic switch from glycolysis to fatty acid oxidation in cardiomyocytes. Importantly, we generated transcriptional profiles specific to cell division and endoreplication in cardiomyocytes at different developmental stages that may facilitate the identification of genes important for adult cardiomyocyte proliferation and heart regeneration. In conclusion, the FUCCI mouse provides a valuable system to study cardiomyocyte cell cycle activity at single cell resolution that can help to decipher the switch from cardiomyocyte proliferation to endoreplication, and to revert this process to facilitate endogenous repair.
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| 3. |
- Bergmann, Olaf, et al.
(author)
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Cardiac regeneration in vivo: Mending the heart from within?
- 2014
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In: Stem Cell Research. - : Elsevier BV. - 1876-7753 .- 1873-5061. ; 13:3, s. 523-531
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Research review (peer-reviewed)abstract
- A growing body of evidence has shown that the heart is not terminally differentiated but continues to renew its cardiomyocytes even after the neonatal period. This new view of the heart increases hope for changing the strategy for treating cardiac injuries toward regenerative approaches. However, the magnitude and clinical significance of this process in homeostasis and disease and the underlying cellular and molecular mechanisms have been heavily debated. Numerous candidates for so-called cardiac stem cells (CSCs) have been proposed, but the different characteristics of these candidates make it difficult to identify the inherent source of regeneration. In this review, we revisit the field of cardiac stem cells and endogenous regeneration to elaborate how these fields may contribute to future regenerative strategies.
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| 4. |
- Bergmann, Olaf, et al.
(author)
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Cardiomyocyte Renewal in Humans
- 2012
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In: Circulation Research. - 0009-7330 .- 1524-4571. ; 110:1, s. 17-18
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Journal article (other academic/artistic)
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| 5. |
- Bergmann, Olaf, et al.
(author)
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Dynamics of Cell Generation and Turnover in the Human Heart.
- 2015
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In: Cell. - : Elsevier BV. - 1097-4172 .- 0092-8674. ; 161:7, s. 1566-1575
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Journal article (peer-reviewed)abstract
- The contribution of cell generation to physiological heart growth and maintenance in humans has been difficult to establish and has remained controversial. We report that the full complement of cardiomyocytes is established perinataly and remains stable over the human lifespan, whereas the numbers of both endothelial and mesenchymal cells increase substantially from birth to early adulthood. Analysis of the integration of nuclear bomb test-derived (14)C revealed a high turnover rate of endothelial cells throughout life (>15% per year) and more limited renewal of mesenchymal cells (<4% per year in adulthood). Cardiomyocyte exchange is highest in early childhood and decreases gradually throughout life to <1% per year in adulthood, with similar turnover rates in the major subdivisions of the myocardium. We provide an integrated model of cell generation and turnover in the human heart. VIDEO ABSTRACT.
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| 6. |
- Bergmann, Olaf, et al.
(author)
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Evidence for Cardiomyocyte Renewal in Humans
- 2009
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In: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 324:5923, s. 98-102
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Journal article (peer-reviewed)abstract
- It has been difficult to establish whether we are limited to the heart muscle cells we are born with or if cardiomyocytes are generated also later in life. We have taken advantage of the integration of carbon-14, generated by nuclear bomb tests during the Cold War, into DNA to establish the age of cardiomyocytes in humans. We report that cardiomyocytes renew, with a gradual decrease from 1% turning over annually at the age of 25 to 0.45% at the age of 75. Fewer than 50% of cardiomyocytes are exchanged during a normal life span. The capacity to generate cardiomyocytes in the adult human heart suggests that it may be rational to work toward the development of therapeutic strategies aimed at stimulating this process in cardiac pathologies.
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| 7. |
- Bergmann, Olaf Ingmar
(author)
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Studies on myocardial regeneration
- 2010
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Doctoral thesis (other academic/artistic)abstract
- Heart disease is one of the leading causes of adult and child morbidity and mortality. The underlying pathology leads typically to a loss of functional cardiomyocytes that causes heart failure. Because of the insufficient regenerative capacity of the human heart, cardiomyocytes have been thought to be incapable of renewing after the postnatal period. In Paper I, we investigated the capacity of the human heart to generate cardiomycytes. We have taken advantage of the integration of the carbon isotope 14C (carbon-14), generated by nuclear bomb tests during the Cold War, into DNA to establish the age of cardiomyocytes in humans. Using cardiac Troponin T and I and pericentriolar protein 1 (PCM-1) as a specific marker to isolate cardiomyocyte nuclei by flow cytometry (Paper I and II). We report that cardiomyocytes renew, with a gradual decrease from 1% turning over annually at the age of 25 to 0.45% at the age of 75. Fewer than 50% of cardiomyocytes are exchanged during a normal life span. The capacity to generate cardiomyocytes in the adult human heart suggests that it may be rational to work toward the development of therapeutic strategies aimed at stimulating this process in cardiac pathologies. After cardiac infarction the formation of inappropriate scar tissue and cardiac remodeling further contribute to cardiac dysfunction. We provide evidence in Paper III, that inhibition of PDGF signalling reduces scar formation and an augmentation of cardiomyogenesis modulated by increased neoangiogenesis. These findings points to the possibility to therapeutically exploit physiological cardiomyocyte renewal by better understanding processes that modulate cardiac regeneration after heart infarction.
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| 8. |
- Bergmann, Olaf, et al.
(author)
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Isolation of Cardiomyocyte Nuclei from Post-mortem Tissue.
- 2012
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In: Journal of Visualized Experiments. - : MyJove Corporation. - 1940-087X. ; :65
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Journal article (peer-reviewed)abstract
- Identification of cardiomyocyte nuclei has been challenging in tissue sections as most strategies rely only on cytoplasmic marker proteins(1). Rare events in cardiac myocytes such as proliferation and apoptosis require an accurate identification of cardiac myocyte nuclei to analyze cellular renewal in homeostasis and in pathological conditions(2). Here, we provide a method to isolate cardiomyocyte nuclei from post mortem tissue by density sedimentation and immunolabeling with antibodies against pericentriolar material 1 (PCM-1) and subsequent flow cytometry sorting. This strategy allows a high throughput analysis and isolation with the advantage of working equally well on fresh tissue and frozen archival material. This makes it possible to study material already collected in biobanks. This technique is applicable and tested in a wide range of species and suitable for multiple downstream applications such as carbon-14 dating(3), cell-cycle analysis(4), visualization of thymidine analogues (e.g. BrdU and IdU)(4), transcriptome and epigenetic analysis.
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| 9. |
- Bergmann, Olaf, et al.
(author)
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Turnover of Human Cardiomyocytes
- 2008
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In: Circulation Research. - 0009-7330. ; 103:12, s. 1494-1495
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Conference paper (peer-reviewed)
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| 10. |
- Heinke, Paula, et al.
(author)
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Diploid hepatocytes drive physiological liver renewal in adult humans
- 2022
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In: CELL SYSTEMS. - : Elsevier. - 2405-4712 .- 2405-4720. ; 13:6, s. 499-
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Journal article (peer-reviewed)abstract
- Physiological liver cell replacement is central to maintaining the organ's high metabolic activity, although its characteristics are difficult to study in humans. Using retrospective radiocarbon (C-14) birth dating of cells, we report that human hepatocytes show continuous and lifelong turnover, allowing the liver to remain a young organ (average age <3 years). Hepatocyte renewal is highly dependent on the ploidy level. Diploid hepatocytes show more than 7-fold higher annual birth rates than polyploid hepatocytes. These observations support the view that physiological liver cell renewal in humans is mainly dependent on diploid hepatocytes, whereas polyploid cells are compromised in their ability to divide. Moreover, cellular transitions between diploid and polyploid hepatocytes are limited under homeostatic conditions. With these findings, we present an integrated model of homeostatic liver cell generation in humans that provides fundamental insights into liver cell turnover dynamics.
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