Atrial myxomas arise from multipotent cardiac stem cells.

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

doi:10.1093/eurheartj/ehaa156

Abstract

AimsCardiac 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 resultsTwenty-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.ConclusionMyxoma-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.

Highlights

Primary tumours of the heart are rare, with an incidence between 0.0017% and 0.19% in unselected patients at autopsy.[1,2,3] Three quarters of the tumours are benign and nearly half the benign heart tumours are myxomas
These data show that c-kitpos/CD45neg/CD31neg myxomaderived cardiac stem/progenitor cells (CSCs) have many similarities with the normal myocardiumresident c-kitpos/CD45neg/CD31neg CSCs and fulfill the in vitro criteria for myxoma tumour stem cells: they are clonogenic, self-renewing, and multipotent, yet they accumulate a growth deficit over passages, which is consistent with the typical low proliferation index of cardiac myxomas.[10,34]
On the basis of the RNASeq-based miR-nome data above, we have evaluated the effects of the five dysregulated miRs (Figure 5B) on growth, clonogenic and myogenic potential of myxoma-derived CSCs (n=3) through selective gain and loss of function experiments based on the infection of lentiviral particles to transduce green fluorescent protein (GFP) together with a specific miRNA mimic or inhibitor

Summary

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. The oncologic designation of benignity understates the potentially clinical devastating effect this cardiac tumour may impose on the patient. Assessing 23 human cardiac myxomas, we detected within myxoma tissue c-kitpos/ CD45neg/CD31neg cardiac cells expressing stemness and cardiac progenitor cell transcription factors. C-kitpos/ CD45neg/CD31neg cardiac myxoma cells secrete the typical gelatinous matrix of cardiac myxoma. Cardiac myxomas appear to be the first CSC-related human cardiac disease

Introduction

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Discussion