The elucidation of factors that activate the regeneration of the adult mammalian heart is of major scientific and therapeutic importance. Here we found that epicardial cells contain a potent cardiogenic activity identified as follistatin-like 1 (Fstl1). Epicardial Fstl1 declines following myocardial infarction and is replaced by myocardial expression. Myocardial Fstl1 does not promote regeneration, either basally or upon transgenic overexpression. Application of the human Fstl1 protein (FSTL1) via an epicardial patch stimulates cell cycle entry and division of pre-existing cardiomyocytes, improving cardiac function and survival in mouse and swine models of myocardial infarction. The data suggest that the loss of epicardial FSTL1 is a maladaptive response to injury, and that its restoration would be an effective way to reverse myocardial death and remodelling following myocardial infarction in humans.

APJ is shown to be a bifunctional receptor for both mechanical stretch and the endogenous peptide apelin, a finding that is important for the development of APJ agonists to treat heart failure. G-protein-coupled receptors (GPCRs) have been widely implicated in the control of cardiac function. Here, a GPCR known as APJ is shown to be a bifunctional receptor involved in the conversion from increased contractility of the heart to cardiac failure. In response to its ligand apelin, which is known to be cardioprotective, APJ mediates adaptive remodelling. Conversely, stretch-dependent apelin-independent APJ activation accounts for pathological remodelling. These findings are important for the development of APJ agonists as treatments for heart failure. Cardiac hypertrophy is initiated as an adaptive response to sustained overload but progresses pathologically as heart failure ensues1. Here we report that genetic loss of APJ, a G-protein-coupled receptor, confers resistance to chronic pressure overload by markedly reducing myocardial hypertrophy and heart failure. In contrast, mice lacking apelin (the endogenous APJ ligand) remain sensitive, suggesting an apelin-independent function of APJ. Freshly isolated APJ-null cardiomyocytes exhibit an attenuated response to stretch, indicating that APJ is a mechanosensor. Activation of APJ by stretch increases cardiomyocyte cell size and induces molecular markers of hypertrophy. Whereas apelin stimulates APJ to activate Gαi and elicits a protective response, stretch signals in an APJ-dependent, G-protein-independent fashion to induce hypertrophy. Stretch-mediated hypertrophy is prevented by knockdown of β-arrestins or by pharmacological doses of apelin acting through Gαi. Taken together, our data indicate that APJ is a bifunctional receptor for both mechanical stretch and the endogenous peptide apelin. By sensing the balance between these stimuli, APJ occupies a pivotal point linking sustained overload to cardiomyocyte hypertrophy.

Tissue engineering utilizes porous scaffolds as template to guide the new tissue growth. Clinical application of scaffolding biomaterials is hindered by implant-associated infection and impaired in vivo visibility of construct in biomedical imaging modalities. We recently demonstrated the use of a bioengineered type I collagen patch to repair damaged myocardium. By incorporating superparamagnetic iron oxide nanoparticles into this patch, here, we developed an MRI-visible scaffold. Moreover, the embedded nanoparticles impeded the growth of Salmonella bacteria in the patch. Conferring anti-infection and MRI-visible activities to the engineered scaffolds can improve their clinical outcomes and reduce the morbidity/mortality of biomaterial-based regenerative therapies.

Due to the limited self-renewal capacity of cardiomyocytes, the mammalian heart exhibits impaired regeneration and insufficient ability to restore heart function after injury. Cardiovascular tissue engineering is currently considered as a promising alternative therapy to restore the structure and function of the failing heart. Recent evidence suggests that the epicardium may play critical roles in regulation of myocardial development and regeneration. One of the mechanisms that has been proposed for the restorative effect of the epicardium is the specific physiomechanical cues that this layer provides to the cardiac cells. In this article we explore whether a new generation of epicardium-mimicking, acellular matrices can be utilized to enhance cardiac healing after injury. The matrix consists of a dense collagen scaffold with optimized biomechanical properties approaching those of embryonic epicardium. Grafting the epicardial patch onto the ischemic myocardium—promptly after the incidence of infarct—resulted in preserved contractility, attenuated ventricular remodeling, diminished fibrosis, and vascularization within the injured tissue in the adult murine heart.