Multipotent adult resident cardiac stem cells (CSCs) were first identified by the expression of c-kit, the stem cell factor receptor. However, in the adult myocardium c-kit alone cannot distinguish CSCs from other c-kit-expressing (c-kit^pos) cells. The adult heart indeed contains a heterogeneous mixture of c-kit^pos cells, mainly composed of mast and endothelial/progenitor cells. This heterogeneity of cardiac c-kit^pos cells has generated confusion and controversy about the existence and role of CSCs in the adult heart. Here, to unravel CSC identity within the heterogeneous c-kit-expressing cardiac cell population, c-kit^pos cardiac cells were separated through CD45-positive or -negative sorting followed by c-kit^pos sorting. The blood/endothelial lineage-committed (Lineage^pos) CD45^posc-kit^pos cardiac cells were compared to CD45^neg(Lineage^neg/Lin^neg) c-kit^pos cardiac cells for stemness and myogenic properties in vitro and in vivo. The majority (~90%) of the resident c-kit^pos cardiac cells are blood/endothelial lineage-committed CD45^posCD31^posc-kit^pos cells. In contrast, the Lin^negCD45^negc-kit^pos cardiac cell cohort, which represents ⩽10% of the total c-kit^pos cells, contain all the cardiac cells with the properties of adult multipotent CSCs. These characteristics are absent from the c-kit^neg and the blood/endothelial lineage-committed c-kit^pos cardiac cells. Single Lin^negc-kit^pos cell-derived clones, which represent only 1–2% of total c-kit^pos myocardial cells, when stimulated with TGF-β/Wnt molecules, acquire full transcriptome and protein expression, sarcomere organisation, spontaneous contraction and electrophysiological properties of differentiated cardiomyocytes (CMs). Genetically tagged cloned progeny of one Lin^negc-kit^pos cell when injected into the infarcted myocardium, results in significant regeneration of new CMs, arterioles and capillaries, derived from the injected cells. The CSC’s myogenic regenerative capacity is dependent on commitment to the CM lineage through activation of the SMAD2 pathway. Such regeneration was not apparent when blood/endothelial lineage-committed c-kit^pos cardiac cells were injected. Thus, among the cardiac c-kit^pos cell cohort only a very small fraction has the phenotype and the differentiation/regenerative potential characteristics of true multipotent CSCs.

Studying proteins and their structures has an important role for understanding protein functionalities. Recently, due to important results obtained with proteomics, a great interest has been given to interactomics , that is, the study of protein-to-protein interactions, called PPI, or more generally, interactions among macromolecules, particularly within cells. Interactomics means studying, modeling, storing, and retrieving protein-to-protein interactions as well as algorithms for manipulating, simulating, and predicting interactions. PPI data can be obtained from biological experiments studying interactions. Modeling and storing PPIs can be realized by using graph theory and graph data management, thus graph databases can be queried for further experiments. PPI graphs can be used as input for data-mining algorithms, where raw data are binary interactions forming interaction graphs, and analysis algorithms retrieve biological interactions among proteins (i.e., PPI biological meanings). For instance, predicting the interactions between two or more proteins can be obtained by mining interaction networks stored in databases. In this article we survey modeling, storing, analyzing, and manipulating PPI data. After describing the main PPI models, mostly based on graphs, the article reviews PPI data representation and storage, as well as PPI databases. Algorithms and software tools for analyzing and managing PPI networks are discussed in depth. The article concludes by discussing the main challenges and research directions in PPI networks.

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. 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^negCSCs , 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. 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.