A single cell transcriptional roadmap of human pacemaker cell differentiation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA784514 | ENA |
REPOSITORIES: ENA
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Project 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 (SANCM) 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.
2022-09-01 | GSE189782 | GEO
Project 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.
| S-EPMC9553210 | biostudies-literature
Project description:A single cell transcriptional roadmap for cardiopharyngeal fate diversification
| PRJNA389784 | ENA
Project description:The sinoatrial node regulates the heart rate throughout life. Failure of this primary pacemaker results in life-threatening, slow heart rhythm. Despite its important 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 and show that they consist of three subtypes of pacemaker cells, including 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 with a functional pacemaker phenotype. This sinoatrial node pacemaker cell surface marker is highly valuable for stem cell-based disease modelling, drug discovery, cell replacement therapies, as well as the delivery of therapeutics to sinoatrial node cells in vivo using antibody-drug conjugates.
2024-10-30 | GSE279631 | GEO
Project description:The sinoatrial node regulates the heart rate throughout life. Failure of this primary pacemaker results in life-threatening, slow heart rhythm. Despite its important 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 and show that they consist of three subtypes of pacemaker cells, including 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 with a functional pacemaker phenotype. This sinoatrial node pacemaker cell surface marker is highly valuable for stem cell-based disease modelling, drug discovery, cell replacement therapies, as well as the delivery of therapeutics to sinoatrial node cells in vivo using antibody-drug conjugates.
2024-10-30 | GSE279632 | GEO
Project description:The sinoatrial node regulates the heart rate throughout life. Failure of this primary pacemaker results in life-threatening, slow heart rhythm. Despite its important 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 and show that they consist of three subtypes of pacemaker cells, including 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 with a functional pacemaker phenotype. This sinoatrial node pacemaker cell surface marker is highly valuable for stem cell-based disease modelling, drug discovery, cell replacement therapies, as well as the delivery of therapeutics to sinoatrial node cells in vivo using antibody-drug conjugates.
2024-10-30 | GSE279630 | GEO
Project description:Cardiac arrhythmias stemming from abnormal sinoatrial node (SAN) function can lead to sudden death. Developing a biological pacemaker device for treating sick sinus syndrome (SSS) could offer a potential cure. Understanding SAN differentiation is crucial, yet its regulatory mechanism remains unclear. We reanalyzed published RNA-seq data and identified Odz4 as a SAN-specific candidate. In situ hybridization revealed Odz4 expression in the cardiac crescent and throughout the cardiac conduction system (CCS). To assess role of Odz4 in CCS differentiation, we utilized a Tet-Off inducible system for its intracellular domain (ICD). Odz4-ICD exogenously expressing embryonic bodies (EBs) exhibited an increased propensity to develop into pacemaker-like cells with enhanced automaticity and upregulated expression of SAN-specific genes. CellChat and GO analyses unveiled SAN-specific enrichment of ligand-receptor sets, especially Ptn-Ncl, and extracellular matrix components in the Odz4-ICD exogenously expressing group. Our findings underscore the significance of Odz4 in SAN development and offer fresh insights into biological pacemaker establishment
2024-07-07 | GSE271665 | GEO
Project description:ATAC-seq revealed multiple pacemaker cell-specific accessible regions in the genome of pacemaker-like cells
2020-10-23 | GSE146044 | GEO
Project description:The basic two-step terminal differentiation model of the medullary thymic epithelial cell (mTEC) lineage from immature MHCIIlo to mature MHCIIhi mTECs has recently been extended to include a third stage namely the post-Aire MHCIIlo subset as identified by lineage-tracing models. Yet, a suitable surface marker distinguishing the phenotypically overlapping pre- from the post-Aire immature MHCIIlo stage has been lacking. Here, we introduce the lectin Tetragonolobus purpureas agglutinin (TPA) as a novel cell surface marker that allows for such delineation. Based on our data, we derived the following sequence of mTEC differentiation: TPA- MHCIIlo → TPA- MHCIIhi → TPA+ MHCIIhi → TPA+ MHCIIlo. Surprisingly, in the steady-state postnatal thymus most immature TPA- pre-Aire rather than terminally differentiated post-Aire TPA+ MHCIIlo mTECs were marked for apoptosis at an exceptionally high rate of about 70 %. Hence, only the minor cycling fraction of the MHCIIlo subset (< 20 %) potentially qualified as mTEC precursors. FoxN1 expression inversely correlated with the fraction of slow cycling and apoptotic cells within the four TPA subsets. TPA further sub-divided human mTECs, though with different subset distribution. Our revised roadmap emphazises close parallels of terminal mTEC development with that of skin, undergoing an alternative route of cell death namely cornification rather than apoptosis. The high rate of apoptosis in immature pre-Aire mTECs points to a “quality control” step during early mTEC differentiation.
2017-07-28 | GSE84956 | GEO
Project description:Hand2 selectively reorganizes chromatin accessibility to induce pacemaker-like transcriptional reprogramming
| PRJNA511667 | ENA