Open Access

Atrial myxomas arise from multipotent cardiac stem cells

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Date: 24 April 2020
Journal: European Heart Journal , Volume 41 , Issue 45 , Pages 4332 - 4345
Topic: OTHER, VALVULAR, MYOCARDIAL, PERICARDIAL, PULMONARY, CONGENITAL HEART DISEASE, Myocardial Disease
Authors: M. Scalise , M. Torella , F. Marino , M. Ravo , G. Giurato , C. Vicinanza , E. Cianflone , T. Mancuso , I. Aquila , L. Salerno , G. Nassa , V. Agosti , A. De Angelis , K. Urbanek , L. Berrino , P. Veltri , D. Paolino , P. Mastroroberto , M. De Feo , G. Viglietto , A. Weisz , B. Nadal-Ginard , G. Ellison-Hughes , D. Torella

ESC Journals

AbstractAims

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.

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About the contributors

Mariangela Scalise

Role: Author

Michele Torella

Role: Author

Fabiola Marino

Role: Author