Biology subjects

Perez-Pomares, J. M.

Publications and source records attributed to Perez-Pomares, J. M..

4 recordsLinked to original sources

bioRxiv2025

VANGL2 shapes the mouse heart tube from adjacent epithelia and without planar polarity

Disruption of the core Planar Cell Polarity component VANGL2 in mice is associated with congenital heart defects and impaired morphogenesis of the embryonic heart tube. However, the underlying mechanisms have remained unclear. Here we quantified in 3D the heart geometry and adjacent tissue architecture in a series of mutants to reveal a dual role of Vangl2 in shaping the heart tube. Together with cell labelling in the chick, we show that VANGL2 in multicellular junctions promotes second heart field cell rearrangements and thus the elongation of the arterial pole. In addition, apically localised VANGL2 and its downstream actin-binding effector SHROOM3 control the bilateral symmetry of the splanchnic mesoderm caudal to the venous pole. Disorganisation of this midline anchor is associated with a rotation of the heart tube and abnormal left ventricle position. Our work overall uncovers novel specific epithelial roles of VANGL2 unrelated to planar polarity during heart morphogenesis.

developmental biology↗

bioRxiv2024

Characterization and Functional Assessment of Epicardial Secretome: Epicardium-Derived Extracellular Vesicles and Matrix

AimThe epicardium, an epithelial layer covering the heart, plays pivotal roles in embryonic heart development and responses to cardiac damage. Epicardial secreted molecular agents are known to be involved in the regulation of these phenomena, but how this regulation occurs is poorly understood. In this study, we have investigated extracellular vesicle (EV) and extracellular matrix (ECM) components of epicardial secretions using a continuous mouse embryonic epicardial-derived cell (EPIC) line. Methods and resultsEpicardial-derived EVs were isolated using differential ultracentrifugation from EPIC cultured at 1% (EVs-H1%), 5% (EVs-H5%), and 21% oxygen (EVs-N). EVs protein content was determined by tandem mass tag (TMT) proteomic analysis. The results showed that epicardial-derived EVs cargo is sensitive to the oxygen level of their parenteral cells, increasing their content on glycolytic proteins. Moreover, hypoxic-derived EVs were found to both increase EPIC proliferation and affect the metabolism of Primary Human Umbilical Vein Endothelial Cells (HUVECs). On the other hand, epicardial-derived extracellular matrix (EPIC-ECM) was characterized by subjecting decellularized EPIC to shotgun proteomics and comparing it to decellularized perinatal hearts and Matrigel(R). We found that EPIC-ECM composition closely resembles that of embryonic cardiac tissue. Although the structural and basement membrane-associated proteins of EPIC-ECM were similar to those found in Matrigel(R)(R), EPIC-ECM exhibited higher protein diversity and was a more potent inducer of HUVEC proliferation. ConclusionThis work represents the first comprehensive and systematic proteomic analysis of two important components of the epicardial-derived secretome. Our experiments reveal that the epicardium responds to hypoxia by secreting EVs capable of modifying the metabolic responses of surrounding cells. Furthermore, EPIC-ECM promotes endothelial cell proliferation. These findings demonstrate the significant signaling abilities of the epicardial secretome, consistent with reports of endothelial responses following cardiac ischemic damage.

developmental biology↗

bioRxiv2024

Unravelling the molecular activation of the reparative cardiac fibroblasts after myocardial infarction

Activated cardiac fibroblasts (Postn+ CFs) are responsible for the healing of the heart tissue after a myocardial infarction (MI). However, so far little is known about the moment that CFs are activated, and the genes involved in this process. This is especially relevant in the context of CF heterogeneity and their role in the response to the damage. In this context, we have described a subpopulation of activated CFs responsible for the healing scar and for preventing the rupture of the ventricle after the damage: the Reparative Cardiac Fibroblasts (RCFs). Our new data indicate that RCFs directly derived from activated CFs, and this transcriptional shift happens in a close window after damage. Interestingly, our results exhibited two different molecular dynamics that would give rise to this activation and, consequently, the appearance of definitive RCFs. Using bulk RNA-Seq, RNAScope and Spatial Transcriptomics, we anatomically localized some of the genes related to both dynamics in the infarcted heart and highlight the potential role of Aspn as a new marker of this transcriptional transition in mice, pigs and patients.

bioinformatics↗

bioRxiv2022

Origin of congenital coronary arterio-ventricular fistulae from anomalous epicardial and myocardial development

AimsIn this work we investigated the embryonic origin of coronary arterio-ventricular connections, known as coronary artery fistulas (CAF), a congenital heart disease associated to postnatal and adult changes in systemic hemodynamics that may cause cardiac ischemia. Methods and resultswe have used different animal models (mouse and avian embryos) to experimentally model CAF morphogenesis. Conditional Itga4 (alpha 4 integrin) epicardial deletion in mice and cryocauterisation of chick and quail embryonic hearts disrupted epicardial development and ventricular wall growth, two essential events in coronary embryogenesis. Additional transcriptomics and in vitro analyses were performed to better understand how arterio-ventricular connections are originated in the embryonic heart. Our results show myocardial discontinuities in the developing heart of mutant mice presenting epicardial defects and avian embryos submitted to a physical cryodamage of the ventricle. These ventricular discontinuities promote the formation of endocardial pouch-like structures resembling human CAF. The structure of these CAF-like anomalies was compared with histopathological data from a human CAF, showing histomorphological and immunochemical similarities. Both human and mutant mouse hearts showed similar anomalies in the compaction of the ventricular myocardium. In vitro experiments showed the abnormal contact between the epicardium and the endocardium promote the precocious differentiation of epicardial cells to smooth muscle. ConclusionOur work suggests that myocardial discontinuities in the embryonic ventricular wall are a causative of CAF. These discontinuities would promote the early contact of the endocardium with epicardial-derived coronary progenitors at the cardiac surface, leading to ventricular endocardial extrusion, precocious differentiation of coronary smooth muscle cells, and the formation of pouch-like aberrant coronary-like structures in direct connection with the ventricular lumen. Translational perspectiveCongenital coronary artery fistulas (CAFs) lead to complications such as myocardial hypertrophy, endocarditis, heart dilatation and failure. Unfortunately, and despite their clinical relevance, the origins these congenital anomalies remain unknown. In this work, we provide information on the developmental mechanisms involved in the formation of CAFs that is relevant for their early diagnosis and prevention.

developmental biology↗