Cardiac explant-derived cells are regulated by Notch-modulated mesenchymal transition.
BACKGROUND
Progenitor 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).


RESULTS
Explant-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.


CONCLUSIONS
Our study suggests that Notch-mediated reversible EMT process is a mechanism that regulates explant-derived c-Kit+ and c-Kit- cells.
Center for Cardiovascular Research, Banner Sun Health Research Institute, Sun City, Arizona, United States of America.
Liudmila
L
Zakharova
Hikmet
H
Nural-Guvener
Mohamed A
MA
Gaballa
D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D010641:Phenotype; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051881:Receptor, Notch1 / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051881:Receptor, Notch1; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D019009:Proto-Oncogene Proteins c-kit