Atrial Myxomas Arise From Multipotent Myxoid Cardiac Stem Cells

Myxomas, the most common primary tumor of the heart, usually develop in the atria and consist of a myxoid matrix composed of an acid-mucopolysaccharide-rich stroma with polygonal stromal cells scattered throughout the matrix. These benign tumors, despite their rarity, are a research focus because of their clinical presentation and uncertain histogenesis. The objective of this study was to assess whether adult cardiac stem/progenitor cells (CSCs) give rise to myxoma stromal cells and secrete the typical myxoid matrix. 23 collected tumors showed the typical histological features of cardiac atrial myxoma with polygonal cells positive for the myxoma tumor-cell marker, calretinin, dispersed in an abundant myxoid matrix. We detected myxoma cells positive for c-kit (c-kitpos) but very rare Isl-1 positive cells. Most of these c-kitpos cells were lineage-committed CD45pos/CD31pos cells. However, c-kitpos /CD45neg/CD31neg cardiac myxoma cells expressed stemness and cardiac progenitor cell transcription factors. Some (<10%) of these c-kitpos/ CD45neg/CD31neg/ myxoma cells expressed also calretinin, representing myxoma stromal precursor cells. c-kitpos/CD45neg/CD31neg cardiac myxoma cells secrete in vitro chondroitin-6-sulfate and hyaluronic acid, composing the gelatinous matrix of cardiac myxoma in vivo. In vitro, c-kitpos/CD45neg/CD31neg myxoma cells have stem cell properties being clonogenic, self-renewing and sphere forming. On the other hand, they exhibited an abortive cardiac differentiation potential with significant changes in their mRNA and microRNA transcriptome compared to normal c-kitpos/CD45neg /CD31neg CSCs. Importantly, myxoma-derived CSCs seed human atrial myxoma in xenograft's experiments in NOD/SCID mice. Thus, un-committed c-kitpos/CD45neg /CD31neg cells fulfill the criteria of myxoma stem cells in atrial myxoma. Myxomas appear to be the first CSC-related human cardiac disease.