Angiotensin II promotes differentiation of mouse c-kit-positive cardiac stem cells into pacemaker-like cells

Abstract

Cardiac stem cells (CSCs) can differentiate into cardiac muscle-like cells; however, it remains unknown whether CSCs may possess the ability to differentiate into pacemaker cells. The aim of the present study was to determine whether angiotensin II (Ang II) could promote the specialization of CSCs into pacemaker-like cells. Mouse CSCs were treated with Ang II from day 3–5, after cell sorting. The differentiation potential of the cells was then analyzed by morphological analysis, flow cytometry, reverse transcription-polymerase chain reaction, immunohistochemistry and patch clamp analysis. Treatment with Ang II resulted in an increased number of cardiac muscle-like cells (32.7±4.8% vs. 21.5±4.8%; P<0.05), and inhibition of smooth muscle-like cells (6.2±7.3% vs. 20.5±5.1%; P<0.05). Following treatment with Ang II, increased levels of the cardiac progenitor-specific markers GATA4 and Nkx2.5 were observed in the cells. Furthermore, the transcript levels of pacemaker function-related genes, including hyperpolarization-activated cyclic nucleotide-gated (HCN)2, HCN4, T-box (Tbx)2 and Tbx3, were significantly upregulated. Immunofluorescence analysis confirmed the increased number of pacemaker-like cells. The pacemaker current (If) was recorded in the cells derived from CSCs, treated with Ang II. In conclusion, treatment of CSCs with Ang II during the differentiation process modified cardiac-specific gene expression and resulted in the enhanced formation of pacemaker-like cells.

Internal associations and dynamic expression of c-kit and nanog genes in ventricular remodelling induced by adriamycin

“…The immunofluorescence analysis demonstrated that a small number of cells co-expressed c-kit and nanog, results which were concordant with those of our previous studies ( 32 , 33 ). Heart failure not only severely damages the heart muscle cells, it also reduces the number of c-kit-positive cells, nanog-positive cells and stem cells ( 34 , 35 ).…”

AT1R-Mediated Apoptosis of Bone Marrow Mesenchymal Stem Cells Is Associated with mtROS Production and mtDNA Reduction

“…Ang II has been widely used as an inducer to stimulate the differentiation of MSCs to functional cells such as cardiomyocytes, endothelial cells, adipocytes, and smooth muscle-like cells [12–16]. The doses of Ang II usually used to stimulate differentiation of MSCs were from 0.1 μ M to 10 μ M [12–14].…”

Role of angiotensin II in stem cell therapy of cardiac disease

“…74 Stem cells that engraft functionality and differentiations, as well as the embryonic stage differentiation of the progenitor cells, are affected by the RAS. 75 In addition to influencing cellular function and structure in the adult pancreas, local RAS has a major effect on pancreatic stem cells/ progenitor cells (PPC) during development. 1 Pancreatic islet RAS regulates PPC differentiation, after transplantation of MSCs, and thereby enables beneficial outcomes to accomplish permanent normal blood glucose levels in patients with Type 1 diabetes.…”