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Atrial Myxomas Arise From Multipotent Cardiac Stem Cells

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Mariangela Scalise, Michele Torella, Fabiola Marino, Maria Ravo, Giorgi Giurato, Carla Vicinanza, Eleonora Cianflone, Teresa Mancuso, Iolanda Aquila, Luca Salerno, Giovanni Nassa, Valter Agosti, Antonella De Angelis, Konrad Urbanek, Pierangelo Veltri, Donatella Paolino, Pasquale Mastroroberto, Marisa De Feo, Giuseppe Viglietto, Alessandro Weisz & 3 more Bernardo Nadal-Ginard, Georgina M. Ellison-Hughes, Daniele Torella

Original languageEnglish
JournalEuropean Heart Journal
Early online date24 Apr 2020
DOIs
Publication statusE-pub ahead of print - 24 Apr 2020

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Abstract

Aims: Cardiac myxomas usually develop in the atria and consist of an acid-mucopolysaccharide-rich myxoid matrix with polygonal stromal cells scattered throughout. These human benign tumors are a valuable research model because of the rarity of cardiac tumors, their clinical presentation and uncertain origin. Here, we assessed whether human adult cardiac stem/progenitor cells (CSCs) give rise to myxoma stromal cells. Methods and Results: 23 myxomas were collected and processed/analyzed for the presence of multipotent CSCs. We detected myxoma cells positive for c-kit (c-kitpos) but very rare Isl-1 positive cells. Most of the c-kitpos cells were blood lineage-committed CD45pos/CD31pos cells. However, c-kitpos /CD45neg/CD31neg cardiac myxoma cells expressed stemness and cardiac progenitor cell transcription factors. Approximately <10% of the c-kitpos/ CD45neg/CD31neg myxoma cells also expressed calretinin, a characteristic of myxoma stromal cells. In vitro, the c-kitpos/CD45neg/CD31neg myxoma cells secrete chondroitin-6-sulfate and hyaluronic acid, which are the main components of gelatinous myxoma matrix in vivo. In vitro, c-kitpos/CD45neg/CD31neg myxoma cells have stem cell properties being clonogenic, self-renewing and sphere forming. They exhibited an abortive cardiac differentiation potential with significant changes in their mRNA and microRNA transcriptome compared to c-kitpos/CD45neg /CD31neg CSCs isolated from normal myocardial tissue. Importantly, myxoma-derived CSCs but not normal myocardium-derived CSCs, seed human myxoma tumors in xenograft’s in NOD/SCID mice. Conclusion: Myxoma-derived c-kitpos/CD45neg /CD31neg fulfill the criteria expected of atrial myxoma-initiating stem cells. The transcriptome of these cells indicates that they belong to or are derived from the same lineage as the atrial multipotent c-kitpos/CD45neg /CD31neg CSCs. Taken together the data presented here suggests that human myxomas are the first-described CSC-related human cardiac disease.

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