Coup-TFII expression defines two different septum transversum cell compartments crucial to cardiac septation and compact ventricular wall growth

COUP-TFII encodes for an orphan nuclear receptor expressed by multiple embryonic tissues. COUP-TFII functions include the regulation of mesodermal progenitor differentiation and cell fate specification, and is required for completion of cardiovascular development as shown by the early death (E9.5) of COUP-TFII-null mice. In this study, we show that COUP-TFII, which is strongly expressed in the atrial myocardium, is also expressed in two different compartments of the septum transversum (ST, E9.5), a mesodermal folding adjacent to cardiac inflow myocardium. The first ST compartment is COUP-TFII+/Isl1+; cells in this compartment concentrate in the posterior part of the ST, overlap with SHF, and are continuous with the dorsal mesenchymal protrusion (DMP, also known as spina vestibuli). The second compartment is characteristically COUP-TFII+/Isl1-, and comprises the majority of proepicardial cells. To dissect the role of COUP-TFII+ ST cells in cardiac development, we conditionally deleted COUP-TFII in the ST using two different Cre constructs (Wt1Cre; G2-Gata4Cre). We show that COUP-TFII deletion in the ST is most severe in G2-Gata4Cre;COUP-TFII-/- mice, containing various cardiovascular progenitor lineages. Mutant mice display atrial septation and atrioventricular septal defects as well as a severe disruption of compact ventricular myocardial growth and coronary vascularization. We conclude that COUP-TFII plays critical, pleiotropic, tissue-dependent roles during cardiac septation, growth and vascularization.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. Centro Nacional de Investigaciones Cardiovasculares (CNIC-ISCIII

Pericoronary cell response to cardiac damage: blood-borne cells and neurovascular interactions

Durante los últimos 15 años, diferentes laboratorios han descrito la existencia de células madre cardíacas (CSC, del inglés Cardiac Stem Cells) pluripotentes residentes en el intersticio cardíaco. Las CSC, cuyo origen embrionario no ha sido nunca descrito de forma sistemática, fueron caracterizadas por la expresión de un número finito de marcadores moleculares (fundamentalmente c-Kit, Sca1, Bmi1 e Isl1) y su potencial de diferenciación valorado in vitro e in vivo. Diversos estudios concluyeron que las CSC eran capaces de originar distintos tipos celulares cardiovasculares como células endoteliales, células musculares lisas y cardiomiocitos en condiciones de homeostasis y/o tras un daño cardíaco. Esta conclusión permitió considerar a las CSC, al mismo tiempo, como el origen de la renovación de cardiomiocitos durante la vida adulta y como una esperanza para la regeneración terapéutica del corazón enfermo. Sin embargo, diversos estudios han demostrado de manera convincente que, si bien existen células cardíacas residentes que expresan marcadores asociados con la multipotencia, esas células no son pluripotentes y, sobre todo, no tienen capacidad para diferenciarse en cardiomiocitos. Los principales objetivos de esta tesis han sido estudiar las células c-Kit+ y Sca1+ en relación con su origen embrionario, así como su capacidad para interactuar con el microambiente intersticial, en concreto en la banda neurovascular a través de unas moléculas denominadas neurotrofinas. Además, se ha analizado la capacidad de las neurotrofinas para influir en diversos tipos celulares del posible nicho pericoronario. Por último, se ha modificado el microambiente intersticial para examinar la respuesta de estas células en condiciones de deficiencia de neurotrofinas y en condiciones de daño cardíaco

Development of the Myocardial Interstitium.

The space between cardiac myocytes is commonly referred-to as the cardiac interstitium (CI). The CI is a unique, complex and dynamic microenvironment in which multiple cell types, extracellular matrix molecules, and instructive signals interact to crucially support heart homeostasis and promote cardiac responses to normal and pathologic stimuli. Despite the biomedical and clinical relevance of the CI, its detailed cellular structure remains to be elucidated. In this review, we will dissect the organization of the cardiac interstitium by following its changing cellular and molecular composition from embryonic developmental stages to adulthood, providing a systematic analysis of the biological components of the CI. The main goal of this review is to contribute to our understanding of the CI roles in health and disease. Anat Rec, 302:58-68, 2019. © 2018 Wiley Periodicals, Inc

Interacting resident epicardium-derived fibroblasts and recruited bone marrow cells form myocardial infarction scar

Although efforts continue to find new therapies to regenerate infarcted heart tissue, knowledge of the cellular and molecular mechanisms involved remains poor. This study sought to identify the origin of cardiac fibroblasts (CFs) in the infarcted heart to better understand the pathophysiology of ventricular remodeling following myocardial infarction (MI). Permanent genetic tracing of epicardium-derived cell (EPDC) and bone marrow-derived blood cell (BMC) lineages was established using Cre/LoxP technology. In vivo gene and protein expression studies, as well as in vitro cell culture assays, were developed to characterize EPDC and BMC interaction and properties. EPDCs, which colonize the cardiac interstitium during embryogenesis, massively differentiate into CFs after MI. This response is disease-specific, because angiotensin II-induced pressure overload does not trigger significant EPDC fibroblastic differentiation. The expansion of epicardial-derived CFs follows BMC infiltration into the infarct site; the number of EPDCs equals that of BMCs 1 week post-infarction. BMC-EPDC interaction leads to cell polarization, packing, massive collagen deposition, and scar formation. Moreover, epicardium-derived CFs display stromal properties with respect to BMCs, contributing to the sustained recruitment of circulating cells to the damaged zone and the cardiac persistence of hematopoietic progenitors/stem cells after MI. EPDCs, but not BMCs, are the main origin of CFs in the ischemic heart. Adult resident EPDC contribution to the CF compartment is time- and disease-dependent. Our findings are relevant to the understanding of post-MI ventricular remodeling and may contribute to the development of new therapies to treat this diseas

Bmi1-Progenitor Cell Ablation Impairs the Angiogenic Response to Myocardial Infarction

Objective- Cardiac progenitor cells reside in the heart in adulthood, although their physiological relevance remains unknown. Here, we demonstrate that after myocardial infarction, adult Bmi1+ (B lymphoma Mo-MLV insertion region 1 homolog [PCGF4]) cardiac cells are a key progenitor-like population in cardiac neovascularization during ventricular remodeling. Approach and Results- These cells, which have a strong in vivo differentiation bias, are a mixture of endothelial- and mesenchymal-related cells with in vitro spontaneous endothelial cell differentiation capacity. Genetic lineage tracing analysis showed that heart-resident Bmi1+ progenitor cells proliferate after acute myocardial infarction and differentiate to generate de novo cardiac vasculature. In a mouse model of induced myocardial infarction, genetic ablation of these cells substantially deteriorated both heart angiogenesis and the ejection fraction, resulting in an ischemic-dilated cardiac phenotype. Conclusions- These findings imply that endothelial-related Bmi1+ progenitor cells are necessary for injury-induced neovascularization in adult mouse heart and highlight these cells as a suitable therapeutic target for preventing dysfunctional left ventricular remodeling after injury

Bmi1-Progenitor Cell Ablation Impairs the Angiogenic Response to Myocardial Infarction.

Objective- Cardiac progenitor cells reside in the heart in adulthood, although their physiological relevance remains unknown. Here, we demonstrate that after myocardial infarction, adult Bmi1+ (B lymphoma Mo-MLV insertion region 1 homolog [PCGF4]) cardiac cells are a key progenitor-like population in cardiac neovascularization during ventricular remodeling. Approach and Results- These cells, which have a strong in vivo differentiation bias, are a mixture of endothelial- and mesenchymal-related cells with in vitro spontaneous endothelial cell differentiation capacity. Genetic lineage tracing analysis showed that heart-resident Bmi1+ progenitor cells proliferate after acute myocardial infarction and differentiate to generate de novo cardiac vasculature. In a mouse model of induced myocardial infarction, genetic ablation of these cells substantially deteriorated both heart angiogenesis and the ejection fraction, resulting in an ischemic-dilated cardiac phenotype. Conclusions- These findings imply that endothelial-related Bmi1+ progenitor cells are necessary for injury-induced neovascularization in adult mouse heart and highlight these cells as a suitable therapeutic target for preventing dysfunctional left ventricular remodeling after injury