Journal
EUROPEAN HEART JOURNAL
Volume 41, Issue 45, Pages 4332-+Publisher
OXFORD UNIV PRESS
DOI: 10.1093/eurheartj/ehaa156
Keywords
Myxoma; Tumour histogenesis; Adult cardiac stem cells; RNASeq; MicroRNA
Categories
Funding
- Italian Association for Cancer Research (AIRC) [MFAG-2008, IG-23068]
- Ministry of Education, University and Research [2015ZTT5KB_004, RBFR12I3KA]
- Italian Ministry of Health Finalized Research [GR-2010-2318945]
- Regione Campania, POR Campania FESR
- Progetto GENOMAeSALUTE [CUP: B41C17000080007]
- Progetto RarePlatNet [CUP: B63D18000380007]
- Medical Research Council [MR/P026508/1]
- MRC [MR/P026508/1] Funding Source: UKRI
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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-kit(pos)) but very rare Isl-1 positive cells. Most of the c-kit(pos) cells were blood lineage-committed CD45(pos)/CD31(pos) cells. However, c-kit(pos)/CD45(neg)/CD31(neg) cardiac myxoma cells expressed stemness and cardiac progenitor cell transcription factors. Approximately <= 10% of the c-kit(pos)/CD45(neg)/CD31(neg) myxoma cells also expressed calretinin, a characteristic of myxoma stromal cells. In vitro, the c-kit(pos)/CD45(neg)/CD31(neg) myxoma cells secrete chondroitin-6-sulfate and hyaluronic acid, which are the main components of gelatinous myxoma matrix in vivo. In vitro, c-kit(pos)/CD45(neg)/CD31(neg) 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-kit(pos)/CD45(neg)/CD31(neg)CSCs, 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-kit(pos)/CD45(neg)/CD31(neg) 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-kit(pos)/CD45(neg)/CD31(neg) 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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