Cardiac Stem Cells Differentiate into Sinus Node-Like Cells

Abstract

The advent of stem cell therapy brings about the hope to restore the loss of cardiac pacemaker cells. However, it is largely unknown whether cardiac stem cells are able to differentiate into pacemaker cells. The purpose of this study was to determine whether the heart of large juvenile mammals contains cardiac stem cells (CSCs), which are suitable as seed cells for restoration of cardiac pacemaker cell. The c-kit + CSCs were isolated from one-month-old mongrel dogs. CSCs that we sorted were self-renewing, and they could proliferate by clonal expansion. CSCs could differentiate into cardiac muscle, smooth muscle and endothelial cells at rates of 10.5 ± 4.2%, 13.5 ± 5.1% and 12.9 ± 3.5%, respectively, at week 4, as judged by the expression of respective differentiation markers: cardiac troponin I, smooth muscle actin, and CD31. At week 8, the differentiation rates were further increased to 23.2 ± 3.6%, 25.9 ± 6.6% and 28.3 ± 6.1% (P < 0.05 for each marker). Some of cells derived from CSCs could express cardiac transcription factor GATA-4 after week 2 and express pacing-related genes, including hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) and HCN4 after week 4. Importantly, a fraction of CSCs demonstrated the presence of inward currents that indicate the expression of inward current channels. In conclusion, c-kit + CSCs may differentiate into cardiac muscle cell and sinus node-like cells, suggesting that CSCs would be useful as seed cells in treating sinus bradycardiac disorders or exploring the mechanism of pacemaker activity.

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

“…Cells that are generated from cardiac tissue, express c-kit and differentiate into numerous cell lineages may be regarded as CSCs. A recent study conducted by the authors of the present study, showed that c-kit positive CSCs from dog and rat hearts have the potential to differentiate into sinus node-like cells in vitro ( 3 ). However, the proportion of sinus node-like cells was small and the intrinsic mechanisms behind this kind of differentiation remain to be elucidated.…”

The role of Wnt regulation in heart development, cardiac repair and disease: A tissue engineering perspective

“…Furthermore, Lian and colleagues robustly generated directed differentiation cultures with yields of up to 98% CMs by sequential treatment with a small molecule Wnt agonist, CHIR99021, followed by a small molecule Wnt antagonist, Wnt inhibitor of Wnt production 4 (IWP4) [26,27]. More recently, differentiation strategies further manipulating cellular signaling have shown control over individual cardiac cell types such as atrial, ventricular and nodal cells [28–30]. …”