Atrial Myxomas Arise From Multipotent Cardiac Stem Cells

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 WeiszBernardo Nadal-Ginard, Georgina M. Ellison-Hughes, Daniele Torella

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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 tumours are a valuable research model because of the rarity of cardiac tumours, their clinical presentation and uncertain origin. Here, we assessed whether multipotent cardiac stem/progenitor cells (CSCs) give rise to atrial myxoma tissue. METHODS AND RESULTS: Twenty-three myxomas were collected and analysed 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 while exhibiting an abortive cardiac differentiation potential. Myxoma-derived CSCs possess a mRNA and microRNA transcriptome overall similar to normal myocardium-derived c-kitpos/CD45neg/CD31negCSCs , yet showing a relatively small and relevant fraction of dysregulated mRNA/miRNAs (miR-126-3p and miR-335-5p, in particular). Importantly, myxoma-derived CSCs but not normal myocardium-derived CSCs, seed human myxoma tumours in xenograft's in immunodeficient NOD/SCID mice. CONCLUSION: Myxoma-derived c-kitpos/CD45neg/CD31neg CSCs 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 suggest that human myxomas could be the first-described CSC-related human heart disease.

Original languageEnglish
Pages (from-to)4332-4345
Number of pages14
JournalEuropean Heart Journal
Volume41
Issue number45
Early online date24 Apr 2020
DOIs
Publication statusPublished - 1 Dec 2020

Keywords

  • Myxoma, Tumor Histogenesis, Adult Cardiac Stem Cells, RNASeq, microRNA

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