Induction of human embryonic stem cell derived cardiac pacemaker or chamber-type cardiomyocytes by manipulation of neuregulin signaling
The present invention is directed to methods of producing cardiomyocytes having a nodal/pacemaker phenotype and cardiomyocytes having an atrial/ventricular phenotype. Isolated populations of nodal/pacemaker and atrial/ventricular cardiomyocytes are also disclosed. Methods of treating a subject having cardiac arrhythmia and a subject in need of cardiac tissue repair using the isolated populations of nodal/pacemaker cardiomyocytes and atrial/ventricular cardiomyocytes, respectively, are also disclosed.
1. A composition comprising an isolated population of nodal/pacemaker cardiomyocytes having a spontaneous firing rate of >90 bpm and a slow, biphasic action potential upstroke of <15V/s and an inhibitor of the NRG-1β/ErbB signaling pathway.
2. The composition comprising an isolated population of nodal/pacemaker cardiomyocytes of claim 1 , wherein the inhibitor of the NRG-1β/ErbB signaling pathway is an antibody or a small molecule.
3. The composition comprising an isolated population of nodal/pacemaker cardiomyocytes of claim 2 , wherein the small molecule is AG1478.
4. The composition comprising an isolated population of nodal/pacemaker cardiomyocytes of claim 2 , wherein the antibody comprises an NRG1β antibody.
5. A composition comprising an isolated population of cells comprising at least 30% nodal/pacemaker cardiomyocytes having a spontaneous firing rate of >90 bpm and a slow biphasic action potential upstroke of <15 V/s, wherein the isolated population of cells is produced by contacting human embryonic stem cell derived cardiomyocytes (hESC-CM) with an inhibitor of the NRG-1β/ErbB signaling pathway.
6. The composition comprising an isolated population of nodal/pacemaker cardiomyocytes of claim 5 , wherein the inhibitor of the NRG-1β/ErbB signaling pathway is an antibody or a small molecule.
7. The composition comprising an isolated population of nodal/pacemaker cardiomyocytes of claim 6 , wherein the small molecule is AG1478.
8. The composition comprising an isolated population of nodal/pacemaker cardiomyocytes of claim 6 , wherein the antibody comprises an NRG1β antibody.