Abstract 708: Cardiac Sca-1+ Cells were Differentiated into Endothelial Cells by Leukemia Inhibitory Factor, a Paracrine Cytokine
Background and Aim: Cardiac stem cells have been identified in the adult hearts, and demonstrated to differentiate into cardiomyocytes, smooth muscle cells and endothelial cells, contributing to cardiac repair and regeneration. However, little is known about the regulatory mechanisms for the differentiation of cardiac stem cells. Since various kinds of cytokines play important roles in the maintenance of cardiac homeostasis through paracrine systems, we investigated the biological significances of leukemia inhibitory factor (LIF), an IL-6-related cytokine produced by myocardium, in the differentiation of cardiac stem cells.
Methods and results: Cardiac Sca-1+ cells were prepared from adult murine hearts by magnetic cell sorting system. LIF activated signal transducer and activator of transcription 3 (STAT3, 5.1 ± 0.6 fold, p < 0.05 vs. control) and extracellular signal regulated kinase 1/2 (ERK1/2, 2.4 ± 0.2 fold, p < 0.05 vs. control) in cardiac Sca-1+ cells. RT-PCR analyses demonstrated that LIF induced endothelial specific genes, such as VE-cadherin, Flk-1 and CD31, in cardiac Sca-1+ cells, while neither cardiac muscle nor smooth muscle specific genfes were upregulated. Immuno-cytochemical analyses showed that about 25% of total Sca-1+ cells expressed VE-cadherin and CD31 14 days after LIF stimulation. In cardiac Sca-1+ cells, adenoviral transduction with dominant negative STAT3 abrogated the LIF-induced endothelial differentiation, and the inhibition of ERK1/2 with the MEK1/2 inhibitor U0126 also prevented the endothelial differentiation by LIF.
Conclusion: These data indicate that LIF induces endothelial differentiation of cardiac Sca-1+ cells through STAT3 and ERK1/2. These findings propose that the endothelial differentiation of cardiac stem cells is regulated by myocardial production of IL-6-related cytokines, contributing to neovascularization in the heart.