Abstract 369: Isolation and Characterization of Developmentally and Functionally Discrete Subsets of Cardiac Fibroblasts

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Although cardiac fibroblasts (CF) are the most prominent cell types in the heart, little is known about their origin and development. Fibroblasts play a key role in regulating the normal myocardial function, as well as the adverse remodeling that occurs with injury. Fundamental to understanding cardiac development is the ability to determine when and where CFs are generated, their ancestry, and how they move to reside in their final position. We used novel transgenic mouse models to lineage trace the developmental origin of CFs and their contribution to fibrosis in response to injury. Here, we show that a subset of cardiac fibroblasts is derived from Mesp1-expressing cells (multipotent cardiac progenitor cells that contribute to precursors of both heart fields). Using Mesp1-Cre;mT/mG mice, in which cells derived from Mesp1-expressing cells are indelibly marked by the GFP reporter protein, we demonstrate that approximately 65% of CFs share an embryonic origin with cardiomyocytes, vascular smooth muscle, and endothelial cells. In addition, experimental myocardial fibrosis did change this proportion. In an attempt to identify the source of the fibroblasts that are non-MesP1-derived, we evaluated contribution from: (i) the bone marrow stromal cells and hematopoietic stem cells, (ii) endothelial-to-mesenchymal transition, (iii) circulating cells, and (iv) epicardial-derived cells. Transplantation of GFP-bone marrow into irradiated wildtype mice resulted in an insignificant contribution of stromal-derived fibroblasts in the heart in response to injury. Using Tie2-Cre;mT/mG mice, we did not observe cardiac fibroblasts originating from endothelial cells in injured hearts. Finally, using a parabiotic pair of GFP and wildtype mice where blood chimerism is established, no evidence for homing of circulating fibroblasts to the heart upon injury was noted. However, we provide unequivocal evidence that epicardial-derived cells migrate to myocardium as fibroblasts to contribute to fibrosis. In summary, using lineage-tracing systems, we provide evidence for two sources of fibroblasts in the heart, one that shares an embryonic origin with the cardiovascular lineages and the other from a non-cardiac origin, which is primarily derived from the epicardium.