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Abstract
BackgroundBecause of their regenerative and paracrine abilities, cardiac stem cells (CSCs) are the most appropriate, optimal and promising candidates for the development of cardiac regenerative medicine strategies. However, native and exogenous CSCs in ischemic hearts are exposed to various pro-apoptotic or cytotoxic factors preventing their regenerative and paracrine abilities.Methods and ResultsWe examined the effects of H2O2 on mouse CSCs (mCSCs), and observed that hydrogen peroxide (H2O2) treatment induces mCSCs apoptosis via the caspase 3 pathway, in a dose-dependent manner. We then examined the effects of Wnt1 over-expression on H2O2-induced apoptosis in mCSCs and observed that Wnt1 significantly decreased H2O2-induced apoptosis in mCSCs. On the other hand, inhibition of the canonical Wnt pathway by the secreted frizzled related protein 2 (SFRP2) or knockdown of β-catenin in mCSCs reduced cells resistance to H2O2-induced apoptosis, suggesting that Wnt1 predominantly prevents H2O2-induced apoptosis through the canonical Wnt pathway.ConclusionsOur results provide the first evidences that Wnt1 plays an important role in CSCs’ defenses against H2O2-induced apoptosis through the canonical Wnt1/GSK3β/β-catenin signaling pathway.
Highlights
Flow cytometry showed that 99.460.4% of cells were c-kit+ (Figure 1A), but were negative for CD34 (1.160.42%). As expected, these cells were positive for the control mesenchymal marker CD90 (95.460.7%), CD29 (99.460.5%) and the stemness marker sca-1 (87.462.07%). These results suggested that mouse CSCs (mCSCs), maintaining stemness phenotypic features, displayed some characteristics of the early cardiac phenotype (Figure 1A)
Resistance to H2O2-mediated Apoptosis To further elucidate the role of the Wnt pathway on the prevention of H2O2-induced mCSCs apoptosis, we examined mCSCs apoptosis and GSK3b activity in secreted frizzled related protein 2 (SFRP2)-treated mCSCs
We evaluated caspase 3 protein levels in Wnt-mCSCs treated with Small Interfering RNA (siRNA)-b-catenin, vehicle alone and siRNA-NC, after a treatment with H2O2 (200 mM for 2 h)
Summary
Accumulating evidences during the past decade in both humans and animal models documented the presence of endogenous cardiac stem cells (CSCs) in adult myocardium. [1,2,3,4] In response to local tissue injury, CSCs differentiate into specialized cells, while the pool of stem cells is maintained in time through self-renewal and enhanced proliferation. [5,6] Exogenous CSCs transplantation into 30-day infarcted rat hearts was shown to activate endogenous CSCs, alleviating left ventricular dysfunction. [7] human cardiosphere-derived cells were reported to exhibit paracrine abilities through the secretion of growth factors, resulting in anti-apoptotic effects on surviving cardiomyocytes following their intra-myocardial injection after myocardial infarction MI in mice. [8] because of their direct regenerative and paracrine abilities, the use of CSCs is considered highly promising as the most appropriate and optimal candidate cell type for future cardiac regenerative medicine studies and strategies. Native and exogenous stem cells in ischemic hearts are exposed to various pro-apoptotic and cytotoxic factors. [22] On the other hand, canonical Wnt signaling was shown to promote apoptosis; this pathway is prevented by SFRP2 through direct binding in H9C2 cells. Caspase 3 is synthesized as an inactive proenzyme that is processed in cells undergoing apoptosis by self-proteolysis and/or cleavage by another upstream protease. Because of their regenerative and paracrine abilities, cardiac stem cells (CSCs) are the most appropriate, optimal and promising candidates for the development of cardiac regenerative medicine strategies. Native and exogenous CSCs in ischemic hearts are exposed to various pro-apoptotic or cytotoxic factors preventing their regenerative and paracrine abilities
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