Heterocellularity and Cellular Cross-Talk in the Cardiovascular System

Abstract

Cellular specialization and interactions with other cell types are the essence of complex multicellular life. The orchestrated function of different cell populations in the heart, in combination with a complex network of intercellular circuits of communication, is essential to maintain a healthy heart and its disruption gives rise to pathological conditions. Over the past few years, the development of new biological research tools has facilitated more accurate identification of the cardiac cell populations and their specific roles. This review aims to provide an overview on the significance and contributions of the various cellular components: cardiomyocytes, fibroblasts, endothelial cells, vascular smooth muscle cells, pericytes, and inflammatory cells. It also aims to describe their role in cardiac development, physiology and pathology with a particular focus on the importance of heterocellularity and cellular interaction between these different cell types.

Endothelial TGF-β signaling instructs smooth muscle development in the cardiac outflow tract

“…Surprisingly, we found that alk5 overexpression in ECs was sufficient to restore SMC wall formation. Although these results do not resolve whether ECs are the only cell type in which Alk5 is necessary for OFT morphogenesis, they suggest that the SMC phenotype could be a secondary effect from the crucial cross-talk between these two cell types (Gaengel et al, 2009; Lilly, 2014; Stratman et al, 2017; Perbellini et al, 2018). Supporting the importance of this cross-talk, it has recently been described that pericyte-specific Alk5 deletion causes an enlargement of brain capillaries in mice.…”

Cellular cross-talks in the diseased and aging heart

“…In the heart, EC closely interact with CMs already during development, e.g. by releasing neuregulin, neurofibromatosis type-1 (NF1) and platelet-derived growth factor β (PDGFβ) [6,[46][47][48]. After cardiac injury, a major function of ECs was attributed to the control of immune cell invasion [49] via up-regulation of P-selectin [50] as well as MCP-1 [51] and the restoration of the vascular network to provide oxygen to the ischemic or hypertrophic cardiac tissue.…”

“…Inhibition of VEGF prevented increased capillary density and induced heart failure [44,56]. But EC can also signal back to CM: For example, EC derived endothelin-1 acts in a paracrine manner on CMs (via the ET A receptor) and induces hypertrophy as well as remodeling in the diseased heart [6]. Other EC-derived factors were shown to elicit protective effects on CM.…”

“…Their synchronized contraction maintains a proper cardiac strain that is needed to pump blood through the circulatory system. To maintain cardiac contraction throughout a whole lifespan, CMs are equipped with a very large cytoplasm that is crammed with sarcomeres, the contractile unit of myocytes and mitochondria to meet their high energy demand [6]. The main interaction partners of CMs are neighboring CMs.…”

“…In the present review, we focus on the interplay of immune cells and the three cell populations namely cardiomyocytes (CM), fibroblasts (FB) and endothelial cells (EC) during disease, regeneration and aging. The heterocellular cross-talk in the heart under physiological conditions was recently reviewed by Perbellini et al [6]. The first two chapters will focus on detrimental and beneficial changes in cellular communication as it occurs during cardiac disease and regeneration, while the last chapter will discuss cellular changes during cardiac aging.…”