Key result
NRG-1/ErbB inhibition with AG1478 enhances pacemaker differentiation in rat bone marrow stromal cells.
Why the study?
The role of NRG-1/ErbB signaling in regulating the differentiation of bone marrow stromal cells into sinoatrial node-like cells was unclear.
Inhibiting the endogenous NRG-1/ErbB signaling pathway during the differentiation of rat BMSCs into cardiomyocytes enhances the pacemaker phenotype, potentially via Akt signaling.
The neuregulin-1 (NRG-1)/ErbB signaling pathway is a crucial regulator of cardiac development and plays an important role in the formation of the cardiac special conduction system. To establish a rat bone marrow stromal cell (BMSC) cardiomyocyte (CM)-like differentiation model, BMSCs were treated with 5-azacytidine and fibroblast growth factor basic (FGF-basic) for 24 hours and then cocultured with neonatal rat CMs in a Transwell culture system. The feasibility of regulating the differentiation of BMSCs into sinoatrial node cells by manipulating the NRG-1/ErbB pathway was investigated. Three weeks after induction, reverse transcription-polymerase chain reaction analysis revealed that inhibition of NRG-1/ErbB signaling (using AG1478) greatly enhanced the expression of HCN4, Tbx3, and Tbx2. Additionally, Tbx3 protein levels were higher than in the control group and even produced distinct nodal-type action potentials. The expression of Nkx2.5 in the NRG-1 group (treated with exogenous NRG-1) was higher than the other 2 groups. The expression of phospho-Akt was also increased in the NRG-1 group but decreased in the AG1478 group. Together, these data demonstrate that inhibiting the endogenous NRG-1/ErbB signaling pathway when rat BMSCs differentiate into CMs can greatly enhance the pacemaker phenotype. Akt signaling may be one of the underlying molecular mechanisms responsible for these results.
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Li et al. (2014) studied Differentiation of bone marrow stromal cells into sinus node-like cells. Inhibition of NRG-1/ErbB signaling (using AG1478) vs. Control group and exogenous NRG-1 group was evaluated on Expression of HCN4, Tbx3, and Tbx2 and pacemaker phenotype. Inhibiting the endogenous NRG-1/ErbB signaling pathway using AG1478 during the differentiation of rat bone marrow stromal cells into cardiomyocytes greatly enhanced the pacemaker phenotype.
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