title: Effect of NRG-1/ErbB signaling intervention on the differentiation of bone marrow stromal cells into sinus node-like cells.
abstract: 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.
authors.affiliation: *Department of Cardiology, First Affiliated Hospital, Nanchang University, Nanchang, China; and †Department of Vascular Surgery, Linyi People's Hospital, Shandong, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Bingong
authors.initials: B
authors.lastname: Li
authors.forename: Changlie
authors.initials: C
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Minghui
authors.initials: M
authors.lastname: Zeng
authors.forename: Zeqi
authors.initials: Z
authors.lastname: Zheng
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects*; D002454:Cell Differentiation / Q000502:physiology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D020890:Neuregulin-1 / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D012849:Sinoatrial Node / Q000187:drug effects*; D017154:Stromal Cells / Q000187:drug effects*; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D020890:Neuregulin-1; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D066246:ErbB Receptors