Research overview

• Demonstration that the heart hosts a diverse network of inter-connected non-myocytes (McLellan et al., 2020; Pinto et al., 2016; Skelly et al., 2018). Previous to this work the cellular composition of the heart was not known, and this work challenged the prevailing view of the cellular make-up of the heart. This work is critical for regenerative biology: restoration of the diseased heart to a healthy state requires a detailed understanding of the cells that form it.
• The first single-cell transcriptomic analysis of non-myocytes (Skelly et al., 2018). This work was the first application of the novel technology, single-cell transcriptomics, to survey the intrinsic ‘support’ cells of the adult heart. It revealed important intercellular relationships in the heart and sex differences in gene expression in the female and male heart. It also provided new approaches to profile understudied cell types in the heart.
• The first single-cell transcriptomic analysis of the entire cardiac cell network—muscle cells and those supporting them—in the context of chronic physiological stress (McLellan et al., 2020). This work identified previously undescribed cardiac cell types that emerge in the context of stress to drive heart scarring (‘fibrosis’), and are present in both the mouse and human contexts. These cells are important new targets for therapeutic intervention to ameliorate the development of heart failure. This research also challenged multiple paradigms including: (i) the importance of cell types that were previously long thought to be the primary drivers of the development of cardiac fibrosis; (ii) the role of inflammation in pathological fibrosis; and (iii) the uniformity of cellular stress responses and fibrosis between sexes.
• Studies which reveal the importance of biological sex for cardiac cellular makeup, cellular gene expression and orchestrated cellular responses to stress (McLellan et al., 2020; Skelly et al., 2018; Squiers et al., 2020). This body of work demonstrated that: (i) cardiac cell abundance is sex-dependent; (ii) sex hormones can rapidly and reversible alter the cardiac cellular landscape; (iii) gene expression and phenotypes of almost all cardiac cells are dependent on biological sex; (iv) stress responses of disparate cardiac cells, cardiac fibrosis and inflammation are dependent upon biological sex.
• Demonstration that the heart hosts an abundant and diverse network of cardiac immune cells called macrophages (Pinto et al., 2012). Prior to this research nothing was known of ‘resident’ macrophages of the heart. A. Prof. Pinto has also demonstrated how macrophage numbers are spatially and temporally regulated (McLellan et al., 2020; Pinto et al., 2014; Skelly et al., 2018).