From epiblast to mesoderm: elaboration of a fate map for cardiovascular progenitors

The origin and migration of cardiovascular progenitors have been identified using multiple cell fate mapping techniques monitoring marked epiblast cells through time at carefully defined stages of early gastrulation. These studies have revealed that ordered groups of cells from the epiblast move into the anterior region of the primitive streak, and then migrate anterior laterally to define the first heart field in the mesodermal layer. Subsequently, the right and left components of the first heart field fuse into a single straight heart at the embryonic midline. Additional cells derived from the second heart field are added to the cardiac tube and contribute to further heart development. Heterotopic and heterochronic transplantation studies have revealed that cardiac precursor cells are plastic and do not form a specific subpopulation of the cardiac mesoderm. Specification of the heart fields occurs after ingression of precardiac cells through the primitive streak.

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Ventricular, atrial and outflow tract heart progenitors arise from spatially and molecularly distinct regions of the primitive streak

10.1101/2020.07.12.198994 ◽

2020 ◽

Author(s):

Kenzo Ivanovitch ◽

Pablo Soro-Barrio ◽

Probir Chakravarty ◽

Rebecca A Jones ◽

S. Neda Mousavy Gharavy ◽

...

Keyword(s):

Single Cell ◽

Heart Development ◽

Primitive Streak ◽

Outflow Tract ◽

Lineage Tracing ◽

Molecular Signature ◽

Genetic Lineage ◽

Cardiac Progenitors ◽

Heart Field ◽

Genetic Lineage Tracing

AbstractThe heart develops from two sources of mesoderm progenitors, the first and second heart field (FHF and SHF). Using a single cell transcriptomic assay in combination with genetic lineage tracing, we find the FHF and SHF are subdivided into distinct pools of progenitors in gastrulating mouse embryos at earlier stages than previously thought. Each subpopulation has a distinct origin in the primitive streak. The first progenitors to leave the primitive streak contribute to the left ventricle, shortly after right ventricle progenitor emigrate, followed by the outflow tract and atrial progenitors. Although cells allocated to the outflow tract and atrium leave the primitive streak at a similar stage, they arise from different regions. Outflow tract originate from distal locations in the primitive streak while atrial progenitors are positioned more proximally. Moreover, single cell RNA sequencing demonstrates that the primitive streak cells contributing to the ventricles have a distinct molecular signature from those forming the outflow tract and atrium. We conclude that cardiac progenitors are pre-patterned within the primitive streak and this prefigures their allocation to distinct anatomical structures of the heart. Together, our data provide a new molecular and spatial map of mammalian cardiac progenitors that will support future studies of heart development, function and disease.

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Ventricular, atrial, and outflow tract heart progenitors arise from spatially and molecularly distinct regions of the primitive streak

PLoS Biology ◽

10.1371/journal.pbio.3001200 ◽

2021 ◽

Vol 19 (5) ◽

pp. e3001200

Author(s):

Kenzo Ivanovitch ◽

Pablo Soro-Barrio ◽

Probir Chakravarty ◽

Rebecca A. Jones ◽

Donald M. Bell ◽

...

Keyword(s):

Single Cell ◽

Heart Development ◽

Primitive Streak ◽

Outflow Tract ◽

Lineage Tracing ◽

Molecular Signature ◽

Genetic Lineage ◽

Cardiac Progenitors ◽

Heart Field ◽

Genetic Lineage Tracing

The heart develops from 2 sources of mesoderm progenitors, the first and second heart field (FHF and SHF). Using a single-cell transcriptomic assay combined with genetic lineage tracing and live imaging, we find the FHF and SHF are subdivided into distinct pools of progenitors in gastrulating mouse embryos at earlier stages than previously thought. Each subpopulation has a distinct origin in the primitive streak. The first progenitors to leave the primitive streak contribute to the left ventricle, shortly after right ventricle progenitor emigrate, followed by the outflow tract and atrial progenitors. Moreover, a subset of atrial progenitors are gradually incorporated in posterior locations of the FHF. Although cells allocated to the outflow tract and atrium leave the primitive streak at a similar stage, they arise from different regions. Outflow tract cells originate from distal locations in the primitive streak while atrial progenitors are positioned more proximally. Moreover, single-cell RNA sequencing demonstrates that the primitive streak cells contributing to the ventricles have a distinct molecular signature from those forming the outflow tract and atrium. We conclude that cardiac progenitors are prepatterned within the primitive streak and this prefigures their allocation to distinct anatomical structures of the heart. Together, our data provide a new molecular and spatial map of mammalian cardiac progenitors that will support future studies of heart development, function, and disease.

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Abstract 13269: Reduced Expression of scaRNAs Disrupts Spliceosome Function and Heart Development in Zebrafish and Infants with Tetralogy of Fallot

Circulation ◽

10.1161/circ.130.suppl_2.13269 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Douglas C Bittel ◽

Prakash Patil ◽

Tamayo Uechi ◽

Nataliya Kibiryeva ◽

Jennifer Marshall ◽

...

Keyword(s):

Tetralogy Of Fallot ◽

Heart Development ◽

Messenger Rna ◽

Dynamic Equilibrium ◽

Heart Defects ◽

Large Family ◽

New Paradigm ◽

Splice Isoforms ◽

The Right ◽

Heart Fields

The splicing of messenger RNA plays a fundamental role in regulating vertebrate development and differentiation. Although it is well established that alternative splicing (AS) plays an important role in regulating mammalian heart development, a clear link between misregulated splicing and congenital heart defects has not been shown. We recently reported that more than 50% of genes associated with heart development had significant changes in splice forms in the right ventricle of infants with tetralogy of Fallot (TOF; 14M/7F; all less than 1 yr old). Moreover, there was a significant decrease (30-50%, p<0.05) in the level of 12 scaRNAs. scaRNAs are members of the large family of noncoding small RNAs that are responsible for biochemical modification of specific nucleotides in spliceosomal and ribosomal RNAs. These 12 scaRNAs target two spliceosomal RNAs, U2 and U6. We used primary cells derived from the RV of infants with TOF to show a direct link between scaRNA levels and splice isoforms of several key genes regulating human heart development (e.g., GATA4, NOTCH2, DAAM1, DICER1, MBNL1 and 2). In addition, using available RNA-Seq data, we provide evidence that during zebrafish development, there are dynamic oscillations in scaRNAs and splice isoforms of genes that regulate heart development. We knocked down the expression of two scaRNAs; ACA35 (Scarna1) and U94 (Snord94), in zebrafish and saw a corresponding disruption of heart development. Importantly, there was an accompanying alteration in the ratios of splice isoforms of key cardiac regulatory genes. Based on these combined results, we propose that scaRNAs directly regulate the proficiency of the spliceosome by controlling spliceosomal RNA maturation. This in turn contributes to splice isoform dynamic equilibrium and ultimately heart development. These results are consistent with a failure of normal temporal and spatial splicing patterns during early embryonic development, leading to a breakdown in communication between the first and second heart fields, resulting in conotruncal misalignment and TOF. Our findings represent a new paradigm for understanding congenital cardiac malformations.

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Conotruncal myocardium arises from a secondary heart field

Development ◽

10.1242/dev.128.16.3179 ◽

2001 ◽

Vol 128 (16) ◽

pp. 3179-3188 ◽

Cited By ~ 18

Author(s):

Karen L. Waldo ◽

Donna H. Kumiski ◽

Kathleen T. Wallis ◽

Harriett A. Stadt ◽

Mary. R. Hutson ◽

...

Keyword(s):

Heart Development ◽

Outflow Tract ◽

Heart Tube ◽

In Ovo ◽

Atrioventricular Canal ◽

Lateral Plate ◽

Heart Field ◽

Dorsal Mesocardium ◽

Heart Fields ◽

Secondary Heart Field

The primary heart tube is an endocardial tube, ensheathed by myocardial cells, that develops from bilateral primary heart fields located in the lateral plate mesoderm. Earlier mapping studies of the heart fields performed in whole embryo cultures indicate that all of the myocardium of the developed heart originates from the primary heart fields. In contrast, marking experiments in ovo suggest that the atrioventricular canal, atria and conotruncus are added secondarily to the straight heart tube during looping. The results we present resolve this issue by showing that the heart tube elongates during looping, concomitant with accretion of new myocardium. The atria are added progressively from the caudal primary heart fields bilaterally, while the myocardium of the conotruncus is elongated from a midline secondary heart field of splanchnic mesoderm beneath the floor of the foregut. Cells in the secondary heart field express Nkx2.5 and Gata-4, as do the cells of the primary heart fields. Induction of myocardium appears to be unnecessary at the inflow pole, while it occurs at the outflow pole of the heart. Accretion of myocardium at the junction of the inflow myocardium with dorsal mesocardium is completed at stage 12 and later (stage 18) from the secondary heart field just caudal to the outflow tract. Induction of myocardium appears to move in a caudal direction as the outflow tract translocates caudally relative to the pharyngeal arches. As the cells in the secondary heart field begin to move into the outflow or inflow myocardium,they express HNK-1 initially and then MF-20, a marker for myosin heavy chain. FGF-8 and BMP-2 are present in the ventral pharynx and secondary heart field/outflow myocardium, respectively, and appear to effect induction of the cells in a manner that mimics induction of the primary myocardium from the primary heart fields. Neither FGF-8 nor BMP-2 is present as inflow myocardium is added from the primary heart fields. The addition of a secondary myocardium to the primary heart tube provides a new framework for understanding several null mutations in mice that cause defective heart development.

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The allocation of epiblast cells to the embryonic heart and other mesodermal lineages: the role of ingression and tissue movement during gastrulation

Development ◽

10.1242/dev.124.9.1631 ◽

1997 ◽

Vol 124 (9) ◽

pp. 1631-1642 ◽

Cited By ~ 21

Author(s):

P.P. Tam ◽

M. Parameswaran ◽

S.J. Kinder ◽

R.P. Weinberger

Keyword(s):

Cell Fate ◽

Primitive Streak ◽

Heart Cells ◽

Lateral Plate Mesoderm ◽

Lateral Plate ◽

Tissue Movement ◽

Heart Field ◽

Morphogenetic Event ◽

Extraembryonic Mesoderm

The cardiogenic potency of cells in the epiblast of the early primitive-streak stage (early PS) embryo was tested by heterotopic transplantation. The results of this study show that cells in the anterior and posterior epiblast of the early PS-stage embryos have similar cardiogenic potency, and that they differentiated to heart cells after they were transplanted directly to the heart field of the late PS embryo. That the epiblast cells can acquire a cardiac fate without any prior act of ingression through the primitive streak or movement within the mesoderm suggests that neither morphogenetic event is critical for the specification of the cardiogenic fate. The mesodermal cells that have recently ingressed through the primitive streak can express a broad cell fate that is characteristic of the pre-ingressed cells in the host when they were returned to the epiblast. However, mesoderm cells that have ingressed through the primitive streak did not contribute to the lateral plate mesoderm after transplantation back to the epiblast, implying that some restriction of lineage potency may have occurred during ingression. Early PS stage epiblast cells that were transplanted to the epiblast of the mid PS host embryos colonised the embryonic mesoderm but not the extraembryonic mesoderm. This departure from the normal cell fate indicates that the allocation of epiblast cells to the mesodermal lineages is dependent on the timing of their recruitment to the primitive streak and the morphogenetic options that are available to the ingressing cells at that instance.

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Persistent Ventricle Partitioning in the Adult Zebrafish Heart

Journal of Cardiovascular Development and Disease ◽

10.3390/jcdd8040041 ◽

2021 ◽

Vol 8 (4) ◽

pp. 41

Author(s):

Catherine Pfefferli ◽

Hannah R. Moran ◽

Anastasia Felker ◽

Christian Mosimann ◽

Anna Jaźwińska

Keyword(s):

Lateral Plate Mesoderm ◽

Adult Zebrafish ◽

Lateral Plate ◽

Second Heart Field ◽

Heart Field ◽

Left And Right ◽

First Heart Field ◽

The Right ◽

Physical Boundary ◽

Zebrafish Heart

The vertebrate heart integrates cells from the early-differentiating first heart field (FHF) and the later-differentiating second heart field (SHF), both emerging from the lateral plate mesoderm. In mammals, this process forms the basis for the development of the left and right ventricle chambers and subsequent chamber septation. The single ventricle-forming zebrafish heart also integrates FHF and SHF lineages during embryogenesis, yet the contributions of these two myocardial lineages to the adult zebrafish heart remain incompletely understood. Here, we characterize the myocardial labeling of FHF descendants in both the developing and adult zebrafish ventricle. Expanding previous findings, late gastrulation-stage labeling using drl-driven CreERT2 recombinase with a myocardium-specific, myl7-controlled, loxP reporter results in the predominant labeling of FHF-derived outer curvature and the right side of the embryonic ventricle. Raised to adulthood, such lineage-labeled hearts retain broad areas of FHF cardiomyocytes in a region of the ventricle that is positioned at the opposite side to the atrium and encompasses the apex. Our data add to the increasing evidence for a persisting cell-based compartmentalization of the adult zebrafish ventricle even in the absence of any physical boundary.

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Persistent ventricle partitioning in the adult zebrafish heart

10.1101/2021.03.16.435658 ◽

2021 ◽

Author(s):

Catherine Pfefferli ◽

Hannah R. Moran ◽

Anastasia Felker ◽

Christian Mosimann ◽

Anna Jazwinska

Keyword(s):

Lateral Plate Mesoderm ◽

Adult Zebrafish ◽

Lateral Plate ◽

Second Heart Field ◽

Heart Field ◽

Left And Right ◽

First Heart Field ◽

The Right ◽

Physical Boundary ◽

Zebrafish Heart

The vertebrate heart integrates cells from the early-differentiating first heart field (FHF) and the later-differentiating second heart field (SHF) emerging from the lateral plate mesoderm. In mammals, this process forms the basis for the development of the left and right ventricle chambers and subsequent chamber septation. The single ventricle-forming zebrafish heart also integrates FHF and SHF lineages during embryogenesis, yet the contributions of these two myocardial lineages to the adult zebrafish heart remain incompletely understood. Here, we characterize the myocardial labeling of FHF descendants in both the developing and adult zebrafish ventricle. Expanding previous findings, late gastrulation-stage labeling using drl-driven CreERT2 recombinase with a myocardium-specific, myl7-controlled loxP reporter results in predominant labeling of FHF-derived outer curvature and the right side of the embryonic ventricle. Raised to adulthood, such lineage-labeled hearts retain broad areas of FHF cardiomyocytes in a region of the ventricle that is positioned at the opposite side to the atrium and encompasses the apex. Our data add to the increasing evidence for a persisting cell-based compartmentalization of the adult zebrafish ventricle even in the absence of any physical boundary.

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AI and Migration Management

The Oxford Handbook of Ethics of AI ◽

10.1093/oxfordhb/9780190067397.013.49 ◽

2020 ◽

pp. 768-787

Author(s):

Petra Molnar

Keyword(s):

Human Rights ◽

New Technologies ◽

Forced Migration ◽

Fundamental Rights ◽

International Human Rights Law ◽

Privacy Rights ◽

International Regulation ◽

Development Technology ◽

And Migration ◽

The Right

This chapter focuses on how technologies used in the management of migration—such as automated decision-making in immigration and refugee applications and artificial intelligence (AI) lie detectors—impinge on human rights with little international regulation, arguing that this lack of regulation is deliberate, as states single out the migrant population as a viable testing ground for new technologies. Making migrants more trackable and intelligible justifies the use of more technology and data collection under the guide of national security, or even under tropes of humanitarianism and development. Technology is not inherently democratic, and human rights impacts are particularly important to consider in humanitarian and forced migration contexts. An international human rights law framework is particularly useful for codifying and recognizing potential harms, because technology and its development are inherently global and transnational. Ultimately, more oversight and issue specific accountability mechanisms are needed to safeguard fundamental rights of migrants, such as freedom from discrimination, privacy rights, and procedural justice safeguards, such as the right to a fair decision maker and the rights of appeal.

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Crosstalk between MUC1 and VEGF in angiogenesis and metastasis: a review highlighting roles of the MUC1 with an emphasis on metastatic and angiogenic signaling

Cancer Cell International ◽

10.1186/s12935-021-01899-8 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Farnaz Khodabakhsh ◽

Parnaz Merikhian ◽

Mohammad Reza Eisavand ◽

Leila Farahmand

Keyword(s):

Tumor Growth ◽

Signaling Pathways ◽

Cell Fate ◽

Endothelial Cell Proliferation ◽

Mucin 1 ◽

Signaling Transduction ◽

Growth And Survival ◽

Angiogenic Proteins ◽

Angiogenic Effect ◽

And Migration

AbstractVEGF and its receptor family (VEGFR) members have unique signaling transduction system that play significant roles in most pathological processes, such as angiogenesis in tumor growth and metastasis. VEGF-VEGFR complex is a highly specific mitogen for endothelial cells and any de-regulation of the angiogenic balance implicates directly in endothelial cell proliferation and migration. Moreover, it has been shown that overexpressing Mucin 1 (MUC1) on the surface of many tumor cells resulting in upregulation of numerous signaling transduction cascades, such as growth and survival signaling pathways related to RTKs, loss of cell-cell and cell-matrix adhesion, and EMT. It promotes gene transcription of pro-angiogenic proteins such as HIF-1α during periods of oxygen scarcity (hypoxia) to enhance tumor growth and angiogenesis stimulation. In contrast, the cytoplasmic domain of MUC1 (MUC1-C) inhibits apoptosis, which in turn, impresses upon cell fate. Besides, it has been established that reduction in VEGF expression level correlated with silencing MUC1-C level indicating the anti-angiogenic effect of MUC1 downregulation. This review enumerates the role of MUC1-C oncoprotein and VEGF in angiogenesis and metastasis and describes several signaling pathways by which MUC1-C would mediate the pro-angiogenic activities of cancer cells.

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