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A single cell transcriptional roadmap of human pacemaker cell differentiation

Each heartbeat is triggered by the sinoatrial node (SAN), the primary pacemaker of the heart. Studies in 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...

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Autores principales: Wiesinger, Alexandra, Li, Jiuru, Fokkert, Lianne, Bakker, Priscilla, Verkerk, Arie O, Christoffels, Vincent M, Boink, Gerard JJ, Devalla, Harsha D
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9553210/
https://www.ncbi.nlm.nih.gov/pubmed/36217819
http://dx.doi.org/10.7554/eLife.76781
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author Wiesinger, Alexandra
Li, Jiuru
Fokkert, Lianne
Bakker, Priscilla
Verkerk, Arie O
Christoffels, Vincent M
Boink, Gerard JJ
Devalla, Harsha D
author_facet Wiesinger, Alexandra
Li, Jiuru
Fokkert, Lianne
Bakker, Priscilla
Verkerk, Arie O
Christoffels, Vincent M
Boink, Gerard JJ
Devalla, Harsha D
author_sort Wiesinger, Alexandra
collection PubMed
description Each heartbeat is triggered by the sinoatrial node (SAN), the primary pacemaker of the heart. Studies in 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, especially of human pacemaker cell development, are poorly understood. Here, we performed single cell RNA sequencing (scRNA-seq) and trajectory inference on human induced pluripotent stem cells (hiPSCs) differentiating to SAN-like cardiomyocytes (SANCMs) to construct a roadmap of transcriptional changes and lineage decisions. In differentiated SANCM, we identified distinct clusters that closely resemble different subpopulations of the in vivo SAN. Moreover, the presence of a side population of proepicardial cells suggested their shared ontogeny with SANCM, as also reported in vivo. Our results demonstrate that the divergence of SANCM and proepicardial lineages is determined by WNT signaling. Furthermore, we uncovered roles for TGFβ and WNT signaling in the branching of transitional and head SANCM subtypes, respectively. These findings provide new insights into the molecular processes involved in human pacemaker cell differentiation, opening new avenues for complex disease modeling in vitro and inform approaches for cell therapy-based regeneration of the SAN.
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spelling pubmed-95532102022-10-12 A single cell transcriptional roadmap of human pacemaker cell differentiation Wiesinger, Alexandra Li, Jiuru Fokkert, Lianne Bakker, Priscilla Verkerk, Arie O Christoffels, Vincent M Boink, Gerard JJ Devalla, Harsha D eLife Developmental Biology Each heartbeat is triggered by the sinoatrial node (SAN), the primary pacemaker of the heart. Studies in 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, especially of human pacemaker cell development, are poorly understood. Here, we performed single cell RNA sequencing (scRNA-seq) and trajectory inference on human induced pluripotent stem cells (hiPSCs) differentiating to SAN-like cardiomyocytes (SANCMs) to construct a roadmap of transcriptional changes and lineage decisions. In differentiated SANCM, we identified distinct clusters that closely resemble different subpopulations of the in vivo SAN. Moreover, the presence of a side population of proepicardial cells suggested their shared ontogeny with SANCM, as also reported in vivo. Our results demonstrate that the divergence of SANCM and proepicardial lineages is determined by WNT signaling. Furthermore, we uncovered roles for TGFβ and WNT signaling in the branching of transitional and head SANCM subtypes, respectively. These findings provide new insights into the molecular processes involved in human pacemaker cell differentiation, opening new avenues for complex disease modeling in vitro and inform approaches for cell therapy-based regeneration of the SAN. eLife Sciences Publications, Ltd 2022-10-11 /pmc/articles/PMC9553210/ /pubmed/36217819 http://dx.doi.org/10.7554/eLife.76781 Text en © 2022, Wiesinger et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Developmental Biology
Wiesinger, Alexandra
Li, Jiuru
Fokkert, Lianne
Bakker, Priscilla
Verkerk, Arie O
Christoffels, Vincent M
Boink, Gerard JJ
Devalla, Harsha D
A single cell transcriptional roadmap of human pacemaker cell differentiation
title A single cell transcriptional roadmap of human pacemaker cell differentiation
title_full A single cell transcriptional roadmap of human pacemaker cell differentiation
title_fullStr A single cell transcriptional roadmap of human pacemaker cell differentiation
title_full_unstemmed A single cell transcriptional roadmap of human pacemaker cell differentiation
title_short A single cell transcriptional roadmap of human pacemaker cell differentiation
title_sort single cell transcriptional roadmap of human pacemaker cell differentiation
topic Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9553210/
https://www.ncbi.nlm.nih.gov/pubmed/36217819
http://dx.doi.org/10.7554/eLife.76781
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