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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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2022
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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. |
format | Online Article Text |
id | pubmed-9553210 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
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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