Submitted on April 10, 2008
Revised on October 20, 2008
Accepted on November 5, 2008
The Na+/H+ Exchanger Isoform 1 Facilitates Cardiomyocyte Embryonic Stem Cell Differentiation
Xiuju Li1, Pratap Karki Dr.1, Lei Lei2, Huayan Wang2, and Larry Fliegel1*
1 University of Alberta
2 Northwest A and F University
* To whom correspondence should be addressed. E-mail: lfliegel{at}ualberta.ca.
EEmbryonic stem cells provide one potential source of cardiomyocytes for cardiac transplantation however after differentiation of stem cells in vitro, cardiomyocytes usually account for only a minority of cells present. To gain insights into improving cardiomyocyte development from stem cells we examined the role of the Na+/H+ exchanger isoform 1 (NHE1) in cardiomyocyte differentiation. NHE1 protein and message levels were induced by treatment of CGR8 cells to form embryoid bodies and cardiomyocytes. The NHE1 protein was present on the cell surface and NHE1 inhibitor sensitive activity was detected. Inhibition of NHE1 activity during differentiation of CGR8 cells prevented cardiomyocyte differentiation as indicated by decreased message for transcription factors Nkx2-5 and Tbx5, and decreased levels of 
-myosin heavy chain protein. Increased expression of NHE1 from an adenoviral vector facilitated cardiomyocyte differentiation. Similar results were found with cardiomyocyte differentiation of P19 embryonal carcinoma cells. CGR8 cells were treated to induce differentiation but when differentiation was inhibited by dispersing the EB's, myocardial development was inhibited. The results demonstrate that NHE1 activity is important in facilitating stem cell differentiation to cardiomyocyte lineage. Elevated NHE1 expression appears to be triggered as part of the process that facilitates cardiomyocyte development.
