Developmental dynamics of cardiac progenitors and their role in congenital heart defects
Author: Mononen, Mimmi
Date: 2021-03-23
Location: Peter Reichard, Biomedicum, Karolinska Institutet, Solna
Time: 14.00
Department: Inst för cell- och molekylärbiologi / Dept of Cell and Molecular Biology
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Thesis (3.053Mb)
Abstract
Cardiac progenitors are the fundamental building blocks of the heart and play a central role in the pathogenesis of congenital heart defects. Recent single-cell RNA sequencing studies have revealed that the cell populations in both developing and mature heart are more diverse than previously recognized. In particular, there has been a great interest in characterizing the transcriptional signatures of human cardiac progenitor populations and building a roadmap of the early heart lineages. This thesis work is a part of an ongoing effort to map the early human heart progenitors, their developmental dynamics and their role in the pathogenesis of congenital heart defects at a single-cell resolution.
In paper I, we present a single-cell characterization of in vitro cardiac differentiation of human embryonic stem cells to beating cardiomyocytes and other populations. We used single-cell RNA sequencing data integration to compare the in vitro-derived cardiac cells to human embryonic heart, studied the developmental dynamics of cardiac progenitors by building a differentiation roadmap, and investigated the effect of loss of ISL1 transcription factor on the differentiation process. In paper II, we mapped the genetic landscape of non-syndromic Tetralogy of Fallot, a form of complex congenital heart defect, in a cohort of 146 patient-parent trios. We intersected the identified disease-associated genes with single-cell RNA sequencing analysis of in vivo and in vitro human cardiac development generated by us and other laboratories. Interestingly, we could pinpoint cardiac progenitors as a cellular hotspot in cardiac disease pathogenesis. Paper III introduces a novel cardiac progenitor marked by LGR5, which exists both in the human embryonic heart in vivo and the human embryonic stem cell cardiac differentiation system in vitro. The LGR5+ cono-ventricular progenitor population originates from the ISL1+ progenitor pool and populates the cardiac outflow tract, a cardiac region often affected in congenital heart defects.
Taken together, these studies support the importance of cardiac progenitors in the pathogenesis of cardiac abnormalities and explore their developmental dynamics at a singlecell level.
In paper I, we present a single-cell characterization of in vitro cardiac differentiation of human embryonic stem cells to beating cardiomyocytes and other populations. We used single-cell RNA sequencing data integration to compare the in vitro-derived cardiac cells to human embryonic heart, studied the developmental dynamics of cardiac progenitors by building a differentiation roadmap, and investigated the effect of loss of ISL1 transcription factor on the differentiation process. In paper II, we mapped the genetic landscape of non-syndromic Tetralogy of Fallot, a form of complex congenital heart defect, in a cohort of 146 patient-parent trios. We intersected the identified disease-associated genes with single-cell RNA sequencing analysis of in vivo and in vitro human cardiac development generated by us and other laboratories. Interestingly, we could pinpoint cardiac progenitors as a cellular hotspot in cardiac disease pathogenesis. Paper III introduces a novel cardiac progenitor marked by LGR5, which exists both in the human embryonic heart in vivo and the human embryonic stem cell cardiac differentiation system in vitro. The LGR5+ cono-ventricular progenitor population originates from the ISL1+ progenitor pool and populates the cardiac outflow tract, a cardiac region often affected in congenital heart defects.
Taken together, these studies support the importance of cardiac progenitors in the pathogenesis of cardiac abnormalities and explore their developmental dynamics at a singlecell level.
List of papers:
I. Mononen M+, Leung CY+, Xu J, Chien KR*. Trajectory mapping of human embryonic stem cell cardiogenesis reveals lineage branch points and an ISL1 progenitor-derived cardiac fibroblast lineage. Stem Cells. 2020 Oct 1;38(10):1267-1278. +These authors contributed equally, *Corresponding author.
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II. Tang C+, Mononen M+, Hong H+, Jin SC, Zhuang X, Lam W-Y, Garcia- Barceló M-M, Yang Y, Chien K, Tam P, Gruber P*. Whole genome sequencing of a Chinese cohort reveals insights into the genetic landscape and molecular mechanisms of Tetralogy of Fallot. +These authors contributed equally, *Corresponding author. [Manuscript]
III. Sahara M+*, Santoro F+, Sohlmér J, Zhou C, Witman N, Leung CY, Mononen M, Bylund K, Gruber P, Chien KR*. Population and Single-Cell Analysis of Human Cardiogenesis Reveals Unique LGR5 Ventricular Progenitors in Embryonic Outflow Tract. Dev Cell. 2019 Feb 25;48(4):475-490.e7. +These authors contributed equally, *Corresponding author.
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I. Mononen M+, Leung CY+, Xu J, Chien KR*. Trajectory mapping of human embryonic stem cell cardiogenesis reveals lineage branch points and an ISL1 progenitor-derived cardiac fibroblast lineage. Stem Cells. 2020 Oct 1;38(10):1267-1278. +These authors contributed equally, *Corresponding author.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Tang C+, Mononen M+, Hong H+, Jin SC, Zhuang X, Lam W-Y, Garcia- Barceló M-M, Yang Y, Chien K, Tam P, Gruber P*. Whole genome sequencing of a Chinese cohort reveals insights into the genetic landscape and molecular mechanisms of Tetralogy of Fallot. +These authors contributed equally, *Corresponding author. [Manuscript]
III. Sahara M+*, Santoro F+, Sohlmér J, Zhou C, Witman N, Leung CY, Mononen M, Bylund K, Gruber P, Chien KR*. Population and Single-Cell Analysis of Human Cardiogenesis Reveals Unique LGR5 Ventricular Progenitors in Embryonic Outflow Tract. Dev Cell. 2019 Feb 25;48(4):475-490.e7. +These authors contributed equally, *Corresponding author.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Chien, Kenneth
Co-supervisor: Lanner, Fredrik; Riedel, Christian; Leung, Chuen Yan
Issue date: 2021-03-01
Rights:
Publication year: 2021
ISBN: 978-91-8016-158-9
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