Contribution of Extra‐Cardiac Cells in Murine Heart Valves is Age‐Dependent

BACKGROUND: Heart valves are dynamic structures that open and close over 100 000 times a day to maintain unidirectional blood flow during the cardiac cycle. Function is largely achieved by highly organized layers of extracellular matrix that provide the necessary biomechanical properties. Homeostasis of valve extracellular matrix is mediated by valve endothelial and interstitial cell populations, and although the embryonic origins of these cells are known, it is not clear how they are maintained after birth. The goal of this study is to examine the contribution of extracardiac cells to the aortic valve structure with aging using lineage tracing and bone marrow transplantation approaches. METHODS AND RESULTS: Immunohistochemistry and fate mapping studies using CD45‐Cre mice show that the contribution of hematopoietic‐derived cells to heart valve structures begins during embryogenesis and increases with age. Short‐term (6 weeks), CD45‐derived cells maintain CD45 expression and the majority coexpress monocyte markers (CD11b), whereas coexpression with valve endothelial (CD31) and interstitial (Vimentin) cell markers were infrequent. Similar molecular phenotypes are observed in heart valves of irradiated donor mice following transplantation of whole bone marrow cells, and engraftment efficiency in this tissue is age‐dependent. CONCLUSIONS: Findings from this study demonstrate that the percentage of CD45‐positive extracardiac cells reside within endothelial and interstitial regions of heart valve structures increases with age. In addition, bone transplantation studies show that engraftment is dependent on the age of the donor and age of the tissue environment of the recipient. These studies create a foundation for further work defining the role of extracardiac cells in homeostatic and diseased heart valves.