BMP protein-mediated crosstalk between inflammatory cells and human pluripotent stem cell-derived cardiomyocytes.

Following cardiac injury, the ischaemic heart tissue is characterized by the invasion of pro-inflammatory (M1) and pro-healing (M2) macrophages. Any engineered cardiac tissue will inevitably interact with the inflammatory environment found at the site of myocardial infarction at the time of implantation. However, the interactions between the inflammatory and the cardiac repair cells remain poorly understood. Here we recapitulated in vitro some of the important cellular events found at the site of myocardial injury, such as macrophage recruitment and their effect on cardiac differentiation and maturation, by taking into account the involvement of paracrine-mediated signalling. By using a 3D inverted invasion assay, we found that cardiomyocyte (CM) conditioned medium can trigger the recruitment of pro-inflammatory (M1) macrophages, through a mechanism that involves, in part, CM-derived BMP4. Pro-inflammatory (M1) macrophages were also found to affect CM proliferation and differentiation potential, in part due to BMP molecules secreted by macrophages. These effects involved the activation of the canonical outside-in signalling pathways, such as SMAD1,5,8, which are known to be activated during myocardial injury in vivo. In the present study we propose a new role for CM- and macrophage-derived BMP proteins during the recruitment of macrophage subtypes and the maturation of repair cells, representing an important step towards creating a functional cardiac patch with superior therapeutic properties.