RT Journal Article
SR Electronic
T1 A single cell transcriptional roadmap for human pacemaker cell differentiation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.12.28.474383
DO 10.1101/2021.12.28.474383
A1 Alexandra Wiesinger
A1 Jiuru Li
A1 Lianne Fokkert
A1 Priscilla Bakker
A1 Arie O. Verkerk
A1 Vincent M. Christoffels
A1 Gerard J.J. Boink
A1 Harsha D. Devalla
YR 2021
UL http://biorxiv.org/content/early/2021/12/29/2021.12.28.474383.abstract
AB Each heartbeat is triggered by the sinoatrial node, the natural pacemaker of the heart. Animal models have revealed that pacemaker cells share a common progenitor with the (pro)epicardium, and that the pacemaker cardiomyocytes further diversify into “transitional”, “tail” and “head” subtypes. However, the underlying molecular mechanisms are poorly understood. Here, we studied the differentiation of human induced pluripotent stem cells into pacemaker cardiomyocytes. Single cell RNA sequencing identified the presence of myocardial populations resembling subtypes present in the formed sinoatrial node, and in addition revealed a side population of (pro)epicardial cells. Time-course trajectory analysis uncovered a role for WNT signaling in determining myocardial versus proepicardial cell fate. We experimentally demonstrate that presence of WNT signaling prior to the branching point of a common progenitor enhances proepicardial cell differentiation at the expense of myocardial pacemaker cells. Furthermore, we uncover a role for TGFβ and WNT signaling in differentiation towards transitional and head pacemaker subtypes, respectively. Our findings provide new biological insights into human pacemaker differentiation, open avenues for complex disease modeling and inform regenerative approaches.