Abstract

The sinoatrial node regulates the heart rate throughout life. Failure of this primary pacemaker results in life-threatening, slow heart rhythm. Despite its critical function, the cellular and molecular composition of the human sinoatrial node is not resolved. Particularly, no cell surface marker to identify and isolate sinoatrial node pacemaker cells has been reported. Here we use single-nuclei/cell RNA sequencing of fetal and human pluripotent stem cell-derived sinoatrial node cells to reveal that they consist of three subtypes of pacemaker cells: Core Pacemaker, Sinus Venosus, and Transitional Cells. Our study identifies a host of sinoatrial node pacemaker markers including MYH11, BMP4, and the cell surface antigen CD34. We demonstrate that sorting for CD34+ cells from stem cell differentiation cultures enriches for sinoatrial node cells exhibiting a functional pacemaker phenotype. This sinoatrial node pacemaker cell surface marker is highly valuable for stem cell-based disease modeling, drug discovery, cell replacement therapies, and the targeted delivery of therapeutics to sinoatrial node cells in vivo using antibody-drug conjugates.

Lim et al. identify CD34 as a surface marker of the heart’s sinoatrial node pacemaker cells, enabling their isolation from stem cell differentiation cultures, advancing future disease modeling, drug discovery, and biological pacemaker applications.

Details

Title
Single-cell transcriptome analysis reveals CD34 as a marker of human sinoatrial node pacemaker cardiomyocytes
Author
Lim, Amos A. 1 ; Pouyabahar, Delaram 2 ; Ashraf, Mishal 3 ; Huang, Kate 4   VIAFID ORCID Logo  ; Lohbihler, Michelle 1 ; Murareanu, Brandon M. 1 ; Chang, Matthew L. 1 ; Kwan, Maggie 5 ; Alibhai, Faisal J. 5 ; Tran, Thinh 6 ; Mazine, Amine 7 ; Laflamme, Michael A. 8 ; Bader, Gary D. 9   VIAFID ORCID Logo  ; Laksman, Zachary 10   VIAFID ORCID Logo  ; Protze, Stephanie 1   VIAFID ORCID Logo 

1  University Health Network, McEwen Stem Cell Institute, Toronto, Canada (GRID:grid.231844.8) (ISNI:0000 0004 0474 0428); University of Toronto, Department of Molecular Genetics, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938) 
2  University of Toronto, Department of Molecular Genetics, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938); University of Toronto, The Donnelly Centre, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938) 
3  University of British Columbia and St. Paul’s Hospital, Centre for Heart and Lung Innovation, Vancouver, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830); University of British Columbia, School of Biomedical Engineering, Vancouver, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830) 
4  University of British Columbia and St. Paul’s Hospital, Centre for Heart and Lung Innovation, Vancouver, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830); University of British Columbia, Experimental Medicine Program, Vancouver, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830) 
5  University Health Network, McEwen Stem Cell Institute, Toronto, Canada (GRID:grid.231844.8) (ISNI:0000 0004 0474 0428) 
6  University of Toronto, Department of Molecular Genetics, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938); University of Toronto, The Donnelly Centre, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938); Memorial Sloan Kettering Cancer Center, Marie-Josée and Henry R. Kravis Center for Molecular Oncology, New York, USA (GRID:grid.51462.34) (ISNI:0000 0001 2171 9952) 
7  University Health Network, McEwen Stem Cell Institute, Toronto, Canada (GRID:grid.231844.8) (ISNI:0000 0004 0474 0428); University of Toronto, Institute of Biomedical Engineering, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938); University of Toronto, Division of Cardiac Surgery, Department of Surgery, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938) 
8  University Health Network, McEwen Stem Cell Institute, Toronto, Canada (GRID:grid.231844.8) (ISNI:0000 0004 0474 0428); University of Toronto, Department of Laboratory Medicine and Pathobiology, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938) 
9  University of Toronto, Department of Molecular Genetics, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938); University of Toronto, The Donnelly Centre, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938); University of Toronto, Department of Computer Science, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938); University Health Network, Princess Margaret Cancer Centre, Toronto, Canada (GRID:grid.231844.8) (ISNI:0000 0004 0474 0428); Sinai Health System, Lunenfeld-Tanenbaum Research Institute, Toronto, Canada (GRID:grid.492573.e) (ISNI:0000 0004 6477 6457) 
10  University of British Columbia and St. Paul’s Hospital, Centre for Heart and Lung Innovation, Vancouver, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830); University of British Columbia, School of Biomedical Engineering, Vancouver, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830); University of British Columbia, Experimental Medicine Program, Vancouver, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830); University of British Columbia, Department of Medicine, Vancouver, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830) 
Pages
10206
Publication year
2024
Publication date
2024
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-024-54337-4
ProQuest document ID
3133604072
Copyright
© The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.