Regenerative potential of adult human cardiac primitive cells is influenced by chronic pathological conditions: a phenotypic and genetic study.

According to recent hypothesis, pathological processes may deplete the heart of stem cells and uncertainty still prevails as to whether functionally competent primitive cells can be obtained also from failing hearts. The scope of the present study was to assess proliferation, apoptosis, differentiation and commitment of cardiac primitive cells resident in normal (n=8) adult human hearts and in hearts with ischemic cardiomyopathy (n=8). Immunofluorescence and immunoblotting of CD117(+) cells isolated from normal and pathological hearts revealed higher expression of cardiac-specific nuclear and cytoplasmic markers in the latter. Proliferation of CD117(+) cells isolated from hearts with ischemic cardiomyopathy was 3.2±0.7-fold higher (p‹0.005), while the apoptosis induced by oxidative stress was 1.8±0.2-fold higher (p‹0.005) when compared with cells from normal hearts. Gene expression was examined by stem cells specific PCR-based microarray. We confined our analysis to genes with at least a 1.7 fold differential expression and identified 38 downregulated and 39 upregulated genes in CD117(+) cells from failing hearts. The downregulated genes included snail1 homolog, jagged-1 and ephrin b1 that are involved in the early stages of the developmental process; mdm2, p15 and p16 belonging to the cell cycle control functional group, as well as genes from the neurogenesis, skeletal development, bone remodeling and cartilage development functional classes. Upregulated genes, among which OTF2, endothelin receptor, CD105 and MRG1, were involved in developmental maturation, mesenchymal cell differentiation, heart development and circulatory system processes. One major finding emerging from the analysis is the acquired capability of cells from pathological heart of responding to wounding, as well as the upregulation of the response to external stimuli and stress. In comparison with normal cells, those from pathological heart become readily committed to cardiac cell lineages, at the expense of stemness and multipotentiality. Moreover, the epithelial-mesenchymal transition (EMT), which has been proposed as the mechanism behind cardiac stem cells origin, resulted activated, as well as known inducers of EMT, TGFβ and HGF signaling pathways. Cardiac stem cells in the normal and in the pathological heart differ in several respects and the differences reflect the activation of cardiac stem cells pool in the chronic pathological conditions. Given the apparent failure of intrinsic heart regeneration, further studies are warranted to optimize the strategies for cardiac stem cells application in regenerative medicine