Single-cell analysis of cardiogenesis reveals basis for organ-level developmental defects

Soysa, T. Yvanka de; Ranade, Sanjeev S.; Okawa, Satoshi; Ravichandran, Srikanth; Huang, Yu; Salunga, Hazel T.; Schricker, Amelia; Sol, Antonio del; Gifford, Casey A.; Srivastava, Deepak

doi:10.1038/s41586-019-1414-x

Cited by 203 publications

(256 citation statements)

References 28 publications

(34 reference statements)

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“…Unlike scRNA-Seq analysis that identified prominent RV expression of PLN in embryonic mouse hearts 26 , vCM4 were similar in both ventricles.…”

Section: Prelid2mentioning

confidence: 60%

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Cells and gene expression programs in the adult human heart

Litviňuková

Talavera-López

Maatz

et al. 2020

Preprint

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SummaryCardiovascular disease is the leading cause of death worldwide. Advanced insights into disease mechanisms and strategies to improve therapeutic opportunities require deeper understanding of the molecular processes of the normal heart. Knowledge of the full repertoire of cardiac cells and their gene expression profiles is a fundamental first step in this endeavor. Here, using large-scale single cell and nuclei transcriptomic profiling together with state-of-the-art analytical techniques, we characterise the adult human heart cellular landscape covering six anatomical cardiac regions (left and right atria and ventricles, apex and interventricular septum). Our results highlight the cellular heterogeneity of cardiomyocytes, pericytes and fibroblasts, revealing distinct subsets in the atria and ventricles indicative of diverse developmental origins and specialized properties. Further we define the complexity of the cardiac vascular network which includes clusters of arterial, capillary, venous, lymphatic endothelial cells and an atrial-enriched population. By comparing cardiac cells to skeletal muscle and kidney, we identify cardiac tissue resident macrophage subsets with transcriptional signatures indicative of both inflammatory and reparative phenotypes. Further, inference of cell-cell interactions highlight a macrophage-fibroblast-cardiomyocyte network that differs between atria and ventricles, and compared to skeletal muscle. We expect this reference human cardiac cell atlas to advance mechanistic studies of heart homeostasis and disease.

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“…Unlike scRNA-Seq analysis that identified prominent RV expression of PLN in embryonic mouse hearts 26 , vCM4 were similar in both ventricles.…”

Section: Prelid2mentioning

confidence: 60%

“…vCM3 also expressed stress-response genes including ANKRD1 21 , FHL1 22 , DUSP27 23 , XIRP1 and XIRP2. The XIRP proteins interact with cardiac ion channel proteins Nav1.5 and Kv1.5 within intercalated discs, and have been implicated in lethal cardiac arrhythmias prevalent in cardiomyopathies 26,24 .…”

Section: Prelid2mentioning

confidence: 99%

Cells and gene expression programs in the adult human heart

Litviňuková

Talavera-López

Maatz

et al. 2020

Preprint

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“…Besides the mature, atrial, and ventricular cardiomyocytes, there is another Hand2os1 high cardiomyocyte population with a 1.5-fold expression enrichment apparently originating from the Hand2os1 low population. Based on very recent findings of de Soysa et al [14], who identified Hand2 as a specifier of outflow tract cells but not right ventricular cells during embryonal development, we assume that this population represents cells of the outflow tract.…”

Section: Resultsmentioning

confidence: 99%

Single-Nucleus Sequencing of an Entire Mammalian Heart: Cell Type Composition and Velocity

Wolfien

Galow

Müller

et al. 2020

Cells

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Analyses on the cellular level are indispensable to expand our understanding of complex tissues like the mammalian heart. Single-nucleus sequencing (snRNA-seq) allows for the exploration of cellular composition and cell features without major hurdles of single-cell sequencing. We used snRNA-seq to investigate for the first time an entire adult mammalian heart. Single-nucleus quantification and clustering led to an accurate representation of cell types, revealing 24 distinct clusters with endothelial cells (28.8%), fibroblasts (25.3%), and cardiomyocytes (22.8%) constituting the major cell populations. An additional RNA velocity analysis allowed us to study transcription kinetics and was utilized to visualize the transitions between mature and nascent cellular states of the cell types. We identified subgroups of cardiomyocytes with distinct marker profiles. For example, the expression of Hand2os1 distinguished immature cardiomyocytes from differentiated cardiomyocyte populations. Moreover, we found a cell population that comprises endothelial markers as well as markers clearly related to cardiomyocyte function. Our velocity data support the idea that this population is in a trans-differentiation process from an endothelial cell-like phenotype towards a cardiomyocyte-like phenotype. In summary, we present the first report of sequencing an entire adult mammalian heart, providing realistic cell-type distributions combined with RNA velocity kinetics hinting at interrelations.

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“…A differentiation continuum of single cell transcriptomes from CPs in the pSHF to functionally differentiated HT CMs in the heart was apparent ( Figure 1C and Supplemental Figure 2A). The two CP clusters expressed known pSHF genes Isl1, Tbx5 and Arg1 ( Figure 1D) (Cai et al, 2003;de Soysa et al, 2019;Xie et al, 2012) and represented right (CP1) and left (CP2) pSHF populations based on differential expression of the right-sided marker D030025E07Rik/Plyrr lncRNA (Welsh et al, 2015) and left-sided marker Pitx2 (Chengyu Liu, 2002;K. Kitamura, 1999) (Supplemental Figure 2B-D and Supplemental Table 2).…”

Section: A Screen Of Intercellular Signaling Pathway Activity Duringmentioning

confidence: 99%

Hedgehog signaling activates a heterochronic gene regulatory network to control differentiation timing across lineages

Rowton

Perez-Cervantes

Rydeen

et al. 2018

Preprint

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Hedgehog (Hh) signaling acts as a developmental morphogen that contributes to the diversification of cell fates and tissue patterning in multiple embryonic contexts, as well as regulating the proliferation of adult tissue stem cells1-9. Here, we report a novel function of Hh signaling GLI transcription factors (TFs) in directly governing the timing of cellular differentiation, independent of a role in specification or proliferation. Disruption of active Hh signaling in the embryo resulted in reduced expression of a progenitor-specific transcription factor network and the inappropriate activation of cardiac differentiation-specific gene expression programs. Expression of the activating Hh transcription factor, GLI1, a marker and effector of active Hh signaling, is correlated with stem and progenitor states during the differentiation of all three germ layers in mouse and human. Transient induction of GLI1 in mouse embryonic stem cell (mESC)-derived cardiac and neural progenitors delayed the onset of the cardiomyocyte and neuron differentiation programs, respectively, while activating progenitor-specific gene expression. GLI1 expression in cardiac progenitors promoted a shift in chromatin accessibility towards a progenitor-like profile at distal regulatory elements near Hh-dependent genes. Manipulating the balance of active to repressive GLI TF predominance unveiled a molecular switch that determined the activity patterns of progenitor-specific distal cis-regulatory elements in vitro and in vivo. Overriding this switch through forced expression of a repressive GLI TF in cardiac progenitors in vivo caused precocious cardiomyocyte differentiation and Congenital Heart Disease (CHD). Our data suggest that a GLI TF switch at distal regulatory elements maintains progenitor cell status and inhibits premature differentiation through the activation and maintenance of a progenitor-specific regulatory network, thus controlling progenitor differentiation timing. We propose a novel molecular paradigm for progenitor maintenance in diverse cellular contexts by signal-dependent TFs with implications for organ development, regenerative potential, and Hh-driven cancers.

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Single-cell analysis of cardiogenesis reveals basis for organ-level developmental defects

Cited by 203 publications

References 28 publications

Cells and gene expression programs in the adult human heart

Cells and gene expression programs in the adult human heart

Single-Nucleus Sequencing of an Entire Mammalian Heart: Cell Type Composition and Velocity

Hedgehog signaling activates a heterochronic gene regulatory network to control differentiation timing across lineages

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