Adult Cardiac-Resident MSC-like Stem Cells with a Proepicardial Origin

Colony-forming units – fibroblast (CFU-Fs), analogous to those giving rise to bone marrow (BM) mesenchymal stem cells (MSCs), are present in many organs, although the relationship between BM and organ-specific CFU-Fs in homeostasis and tissue repair is unknown. Here we describe a population of adult cardiac-resident CFU-Fs (cCFU-Fs) that occupy a perivascular, adventitial niche and show broad trans-germ layer potency in vitro and in vivo. CRE lineage tracing and embryo analysis demonstrated a proepicardial origin for cCFU-Fs. Furthermore, in BM transplantation chimeras, we found no interchange between BM and cCFU-Fs after aging, myocardial infarction, or BM stem cell mobilization. BM and cardiac and aortic CFU-Fs had distinct CRE lineage signatures, indicating that they arise from different progenitor beds during development. These diverse origins for CFU-Fs suggest an underlying basis for differentiation biases seen in different CFU-F populations, and could also influence their capacity for participating in tissue repair. ► Colony-forming cells (CFU-Fs) akin to those in bone marrow (BM) exist in the heart ► Cardiac CFU-Fs share properties with BM MSCs but are not BM derived ► Lineage tracing shows that heart CFU-Fs are born in the proepicardium in development ► Cardiac, BM, and aorta-derived CFU-Fs have different lineage origins