Cardiac atrial appendage stem cells promote angiogenesis in vitro and in vivo

Cardiac atrial appendage stem cells (CASCs) show extraordinary myocardial differentiation properties, making them ideal candidates for myocardial regeneration. However, since the myocardium is a highly vascularized tissue, revascularization of the ischemic infarct area is essential for functional repair. Therefore, this study assessed if CASCs contribute to cardiac angiogenesis via paracrine mechanisms. First, it was demonstrated that CASCs produce and secrete high levels of numerous angiogenic growth factors, including vascular endothelial growth factor (VEGF), endothelin-1 (ET-1) and insulin-like growth factor binding protein 3 (IGFBP-3). Functional in vitro assays with a human microvascular endothelial cell line (HMEC-1) and CASC CM showed that CASCs promote endothelial cell proliferation, migration and tube formation, the most important steps of the angiogenesis process. Addition of inhibitory antibodies against identified growth factors could significantly reduce these effects, indicating their importance in CASC-induced neovascularization. The angiogenic potential of CASCs and CASC CM was also confirmed in a chorioallantoic membrane assay, demonstrating that CASCs promote blood vessel formation in vivo. In conclusion, this study shows that CASCs not only induce myocardial repair by cardiomyogenic differentiation, but also stimulate blood vessel formation by paracrine mechanisms. The angiogenic properties of CASCs further strengthen their therapeutic potential and make them an optimal stem cell source for the treatment of ischemic heart disease. This work was supported by the Limburg Clinical Research Program (LCRP) UHasselt-ZOL-Jessa (SALK 2014N002124); the foundation Limburg Sterk Merle (LSM-124); Hasselt University; Ziekenhuis Oost-Limburg and Jessa Hospital. In addition, support has been provided via a postdoctoral grant of the FWO (Research Foundation - Flanders) to Annelies Bronckaers, a DOC-PhD grant of Hasselt University for Yanick Fanton and a Ph.D. grant of the Agency for Innovation by Science and Technology in Flanders (IWT) for Leen Willems.