Deciphering the heterogeneity and functional role of the cardiac stroma in health and disease

Heart failure is, in general, an inevitable outcome of ischemic heart disease and various cardiomyopathies. While this is largely attributed to the negligible regenerative capacity of the heart, the deterioration of cardiac function is driven by a myriad of dysregulated processes that culminate in chronic remodeling of the heart. In particular, the cardiac stroma, composed of interstitial mesenchymal cells, represents an important component of the cardiac niche and structure. It acts as a “double-edged” entity that plays a vital role in tissue repair and recovery of cardiac function, yet its involvement in driving pathological alterations leading to complete heart failure cannot be excluded. Thus, understanding the cardiac stroma and identifying mechanisms to alter its behaviour hold significant therapeutic potential. Here, we found that the cardiac stroma is a highly heterogeneous population consisted of multiple anatomically and functionally distinct entities. In response to acute ischemic injury, a subset of perivascular stromal cells known as pericytes acquire a transient signature indicative of increased fibrogenic activity and altered vascular maintenance, which is correlated with their dissociation from the vasculature and the ensuing vascular deterioration in the infarct. This regional response is supported by a niche that perpetuates pro-inflammatory, fibrogenic, and anti-angiogenic signaling beyond the completion of the myocardial scar. Dysregulation of the stroma and its secretome also potentiate the functional deterioration of the cardiac muscle. In chronic contexts such as hypertrophic cardiomyopathy, a subset of fibroblasts adopts an activated state similar to that of acute injuries and upregulates IGF-1 signaling to cardiomyocytes, and therefore inducing a hypertrophic response. Moreover, the abrogation of stromal signals regulating vascular growth and maintenance is indicative of compromised coronary circulation. Collectively, our work underlines the importance to develop strategies that target specific stromal populations and incorporate spatial considerations for effective treatment of cardiac pathologies.