Single cell transcriptional profiling reveals cellular diversity, communication, and sexual dimorphism in the mouse heart

Abstract

INTRODUCTORY PARAGRAPHCharacterization of the cardiac cellulome—the network of cells that form the heart—is essential for understanding cardiac development and normal organ function, and for formulating precise therapeutic strategies to combat heart disease. Recent studies have challenged assumptions about both the cellular composition1 and functional significance of the cardiac non-myocyte cell pool, with unexpected roles identified for resident fibroblasts2 and immune cell populations3,4. In this study, we characterized single-cell transcriptional profiles of the murine non-myocyte cardiac cellular landscape using single-cell RNA sequencing (scRNA-Seq). Detailed molecular analyses revealed the diversity of the cardiac cellulome and facilitated the development of novel techniques to isolate understudied cardiac cell populations such as mural cells and glia. Our analyses also revealed networks of intercellular communication as well as extensive sexual dimorphism in gene expression in the heart, most notably demonstrated by the upregulation of immune-sensing and pro-inflammatory genes in male cardiac macrophages. This study offers new insights into the structure and function of the mammalian cardiac cellulome and provides an important resource that will stimulate new studies in cardiac cell biology.

Diastolic dysfunction in a pre-clinical model of diabetes is associated with changes in the cardiac non-myocyte cellular composition

“…and subsequent cardiac exsanguination. As previously described [10][11][12], the thoracic cavity was exposed and right atrium was cut to allow for cardiac perfusion through the left-ventricular apex (PBS, 0.9mM CaCl 2 , 200mM KCl), after which the heart was excised and ventricles were used for ow cytometry.…”

“…Second, we only examined male mice in our study. Given that cardiac pathology is sex-speci c in mice [11,12] and in humans [16,45], cardiac cellular composition and gene expression are sexually-dimorphic [46]. Future work should examine the impact of biological sex in the development of diabetic cardiomyopathy.…”

“…The mammalian heart consists of a diverse range of cell types [10]. Cardiac non-myocytes-comprised of endothelial cells (ECs), resident mesenchymal cells (RMCs) and leukocytes-outnumber myocytes, and are critical for maintaining homeostasis of the heart [10,11]. While a number of recent studies have provided valuable new insight into the disparate roles of non-myocytes in cardiac homeostasis [10,12] and pathological remodelling [13][14][15], the cellular dynamics of non-myocytes during development of diabetes-induced heart failure remains unexplored.…”

CLARA: A web portal for interactive exploration of the cardiovascular cellular landscape in health and disease

“…In the heart, these include myocytes-which form the vast majority of the heart's volume-and non-myocytes, which outnumber myocytes. The application of single-cell flow cytometry and high throughput sequencing methodologies have transformed our understanding of cardiovascular tissue cellularity and, in particular, the heterogeneity of non-myocytes of the heart [1,2]. Single-cell transcriptomics enables joint examination of cellular heterogeneity and gene expression patterns, in addition to revealing shifts in these parameters in context of development or tissue stress.…”

“…Single-cell transcriptomics enables joint examination of cellular heterogeneity and gene expression patterns, in addition to revealing shifts in these parameters in context of development or tissue stress. Recently, multiple single-cell transcriptomic studies have been published-in human and non-human contexts-that have examined the cellular landscape of the heart [2][3][4][5][6] and aorta [7,8]. Collectively, these studies have shown that cell types respond in an orchestrated manner to a range of physiological stressors, and that the cardiovascular tissues are ecosystems of interdependent cell types.…”