Abstract
BackgroundProgenitor cell therapy is emerging as a novel treatment for heart failure. However the molecular mechanisms regulating the generation of cardiac progenitor cells is not fully understood. We hypothesized that cardiac progenitor cells are generated from cardiac explant via a process similar to epithelial to mesenchymal transition (EMT).Methods/FindingsExplant-derived cells were generated from partially digested atrial tissue. After 21 days in culture, c-Kit+ cells were isolated from cell outgrowth. The majority of explant-originated c-Kit+ cells expressed the epicardial marker Wt1. Cardiac cell outgrowth exhibits a temporal up-regulation of EMT-markers. Notch stimulation augmented, while Notch inhibition suppressed, mesenchymal transition in both c-Kit+ and c-Kit- cells. In c-Kit+ cells, Notch stimulation reduced, while Notch inhibition up-regulated pluripotency marker expressions such as Nanog and Sox2. Notch induction was associated with degradation of β-catenin in c-Kit- cells. In contrast, Notch inhibition resulted in β-catenin accumulation, acquisition of epitheloid morphology, and up-regulation of Wnt target genes in c-Kit- cells.ConclusionOur study suggests that Notch-mediated reversible EMT process is a mechanism that regulates explant-derived c-Kit+ and c-Kit- cells.
Highlights
Heart failure after myocardial infarction (MI) is a major public health issue worldwide
We found that the percentage of cells expressing epithelial markers E- cadherin (Ecad) and Wilms tumor 1 (Wt1) [11,19] decreased in culture (3266.2% vs. 4.561.2% for E-cad, and 61.565.3% vs. 4963.% for Wt1 at day 4 vs. day 21, respectively)
After 21 days in culture, BrdU incorporation rate was similar for c-Kit+, E-cad+ and smooth muscle actin (SMA)+ cells (51.066.4%, 41.868.4%, and 34.0611.1% respectively) (Figure 1D, Figure S1) suggesting that fibroblast proliferation rate did not exceed that of other cell sub-population in culture
Summary
Heart failure after myocardial infarction (MI) is a major public health issue worldwide. Epicardial EMT was shown to generate cardiovascular progenitor cells that differentiate into cardiomyocytes [8]. Pathological and physiological EMTs were similar, in that they were governed by similar signaling pathways, regulators, and effector molecules. These pathways include TGF-b, Wnt/b-catenin, Notch, Hedgehog, and others [13,14]. A similar procardiogenic action of Notch had been reported in mesenchymal cells, which was possibly a reiteration of the EMT that occurred during embryonic cardiac development [17]. We hypothesized that cardiac progenitor cells are generated from cardiac explant via a process similar to epithelial to mesenchymal transition (EMT)
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