Biology subjects

van Berlo, J. H.

Publications and source records attributed to van Berlo, J. H..

4 recordsLinked to original sources

bioRxiv2024

Myocardial Endoglin Regulates Cardiomyocyte Proliferation and Cardiac Regeneration

The mammalian heart loses almost all its regenerative potential in the first week of life due to the cessation of the ability of cardiomyocytes to proliferate. In recent years, a number of regulators of cardiomyocyte proliferation have been identified. Despite this, a clear understanding of the regulatory pathways that control cardiomyocyte proliferation and cardiac regeneration is lacking, and there are likely additional regulators to be discovered. Here, we performed a genome-wide screen on fetal murine cardiomyocytes to identify potential novel regulators of cardiomyocyte proliferation. Endoglin was identified as an inhibitor of cardiomyocyte proliferation in vitro. Endoglin knock-down resulted in enhanced DNA synthesis, cardiomyocyte mitosis and cytokinesis in mouse, rat and human cardiomyocytes. Using gene-targeted mice, we confirmed myocardial Endoglin to be important in cardiomyocyte proliferation and cardiac regeneration using gene-targeted mice. Mechanistically, we show that Smad signaling is required for the endoglin-mediated anti-proliferative effects. Our results identify the TGF-{beta} coreceptor Endoglin as a regulator of cardiac regeneration and cardiomyocyte proliferation. SummaryHigh-content function screening is used to identify a novel inhibitor of cardiomyocyte proliferation which can promote mammalian cardiac regeneration.

genetics↗

bioRxiv2024

Macrophage-derived CCL24 promotes fibrosis and worsens cardiac dysfunction during heart failure

Inflammation is a significant risk factor and contributes to cardiovascular disease by driving both adaptive and maladaptive processes. Macrophages are the most abundant immune cells in the heart and play an important role in the remodeling of cardiac tissue. We have previously shown an overall protective function of resident cardiac macrophages after pressure-overloaded injury. However, a subpopulation of resident macrophages also expresses high levels of the profibrotic CC motif chemokine ligand 24 (CCL24), suggesting a dichotomous role in pressure overload-induced cardiac remodeling. Here, we report that following transverse aortic constriction CCL24 knockout (CCL24 KO) mice have improved systolic function, cardiac wall enlargement, as well as increased myocyte surface area and hypertrophy, suggesting that CCL24 disrupts compensatory hypertrophy. TAC-operated CCL24 KO mice also displayed reduced fibrosis and diminished expression of fibrotic genes, implying a pro-fibrotic role for CCL24. Indeed, CCL24 induced the proliferation and activation of primary mouse fibroblasts in a process that required CCR3, the sole G protein-coupled receptor for CCL24. Correspondingly, selective ablation of CCR3 in fibroblasts improved cardiac function and ameliorated fibrosis following pressure overload. Administration of a CCL24 blocking antibody or a CCR3 antagonist both improved cardiac function in pressure-overloaded mice, highlighting the CCL24-CCR3 axis as a potential therapeutic target for heart failure. Finally, CCL24 deficiency improved cardiac function and ameliorated fibrosis during physiological aging. Overall, these results show that macrophage-derived CCL24 aggravates fibrosis via the CCR3 receptor, leading to impaired cardiac function in acute and chronic heart failure.

immunology↗

bioRxiv2021

A microRNA program controls the transition of cardiomyocyte hyperplasia to hypertrophy and stimulates mammalian cardiac regeneration

Myocardial regeneration is restricted to early postnatal life, when mammalian cardiomyocytes still retain the ability to proliferate. The molecular cues that induce cell cycle arrest of neonatal cardiomyocytes towards terminally differentiated adult heart muscle cells remain obscure. Here we report that the miR-106b[~]25 cluster is higher expressed in the early postnatal myocardium and decreases in expression towards adulthood, especially under conditions of overload, and orchestrates the transition of cardiomyocyte hyperplasia towards cell cycle arrest and hypertrophy by virtue of its targetome. In line, gene delivery of miR-106b[~]25 to the mouse heart provokes cardiomyocyte proliferation by targeting a network of negative cell cycle regulators including E2f5, Cdkn1c, Ccne1 and Wee1. Conversely, gene-targeted miR-106b[~]25 null mice display spontaneous hypertrophic remodeling and exaggerated remodeling to overload by derepression of the prohypertrophic transcription factors Hand2 and Mef2d. Taking advantage of the regulatory function of miR-106b[~]25 on cardiomyocyte hyperplasia and hypertrophy, viral gene delivery of miR-106b[~]25 provokes nearly complete regeneration of the adult myocardium after ischemic injury. Our data demonstrate that exploitation of conserved molecular programs can enhance the regenerative capacity of the injured heart.

molecular biology↗

bioRxiv2019

Abcg2-Expressing Side Population Cells Contribute to Cardiomyocyte Renewal through Fusion

The adult mammalian heart has a limited regenerative capacity. Therefore, identification of endogenous cells and mechanisms that contribute to cardiac regeneration is essential for the development of targeted regenerative therapies. The side population (SP) phenotype enriches for stem cells throughout the body, and SP cells have been identified in the heart. We generated a novel Abcg2-driven, genetic lineage-tracing mouse model and show efficient labeling of SP cells. Labeled SP cells give rise to terminally differentiated cells in bone marrow and intestines. In the heart, we find that Abcg2-expressing SP cells contribute to cardiomyocyte labeling, which is further enhanced in response to different forms of cardiac injury. We find that cardiac SP cells fuse with preexisting cardiomyocytes, which stimulates cardiomyocyte cell cycle entry and likely proliferation, instead of directly differentiating into cardiomyocytes. Our findings provide evidence that cardiac SP cells contribute to endogenous cardiac regeneration through cardiomyocyte fusion.

cell biology↗