A single cell transcriptional roadmap of human pacemaker cell differentiation

Area of Science:

• Cardiovascular Biology
• Developmental Biology
• Stem Cell Biology

Background:

• The sinoatrial node (SAN) is the heart's primary pacemaker, with its development poorly understood in humans.
• Pacemaker cells share progenitors with the (pro)epicardium and diversify into subtypes.

Purpose of the Study:

• To construct a roadmap of transcriptional changes during human pacemaker cell differentiation.
• To elucidate the molecular mechanisms governing SAN cell lineage decisions and subtype specification.

Main Methods:

• Single cell RNA sequencing (scRNA-seq) of human induced pluripotent stem cells (hiPSCs) differentiating into SAN-like cardiomyocytes (SANCMs).
• Trajectory inference analysis to model developmental progression and lineage divergence.
• Identification of distinct SANCM subpopulations and their relationship with proepicardial cells.

Main Results:

• Identified distinct SANCM clusters mirroring in vivo SAN subpopulations.
• Confirmed shared ontogeny between SANCM and proepicardial cells.
• Demonstrated WNT signaling's role in SANCM and proepicardial lineage divergence.
• Uncovered TGFβ and WNT signaling roles in transitional and head SANCM subtype branching.

Conclusions:

• Provided a detailed molecular roadmap of human SAN cell development.
• Highlighted the critical roles of WNT and TGFβ signaling in SAN lineage specification and diversification.
• Opened avenues for in vitro disease modeling and cell therapy-based SAN regeneration.