The amphibian second heart field: Xenopus islet-1 is required for cardiovascular development

AbstractCardiac precursor cells (CPCs) in the first heart field (FHF) and the second heart field (SHF) present at both arterial and venous poles assemble to form a cardiac tube in zebrafish. Hippo kinase cascade is essential for proper heart formation; however, it remains elusive how Hippo signal contributes to early cardiac fate determination. We here demonstrate that mutants of large tumor suppressor kinase 1/2 (lats1/2) exhibited an increase in a SHF marker, Islet1 (Isl1)-positive and hand2 promoter-activated venous pole atrial cardiomyocytes (CMs) and that those showed expansion of the domain between between the anterior and the posterior lateral plate mesoderm. Consistently, TEAD-8 dependent transcription was activated in caudal region of the left ALPM cells that gave rise to the venous pole atrial CMs. Yap1/Wwtr1-promoted bmp2b expression was essential for Smad-regulated hand2 expression in the left ALPM, indicating that Hippo signaling restricts the SHF cells originating from the left ALPM that move toward the venous pole.

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Abstract 322: Postnatal Islet-1 Cardioblasts Are of Neural Crest and Not Second Heart-Field Lineage

Circulation Research ◽

10.1161/res.119.suppl_1.322 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Konstantinos E Hatzistergos ◽

Joshua M Hare

Keyword(s):

Neural Crest ◽

Reporter Gene ◽

Embryoid Body ◽

Temporal Analysis ◽

Lineage Tracing ◽

Gene Activity ◽

Reporter Gene Activity ◽

Second Heart Field ◽

Heart Field ◽

Islet 1

Introduction: The transcription factor Islet-1 (Isl1) is expressed in cardiac mesodermal and neural crest (CNC) lineages during cardiogenesis. A pool of Isl1 + cells persist in the perinatal heart (Isl1 + CPCs), some of which are touted as residual second heart-field (SHF)- derived cardioblasts. However, direct lineage-tracing evidence, supporting a SHF over a CNC origin of Isl1 + CPCs, are lacking. Hypothesis: Isl1 + CPCs are of CNC and not SHF lineage. Methods: The Isl1-nLacZ, Wnt1-Cre;tdTomato and Wnt1::FlpE;RC::Fela mice, and iPSCs derived from Wnt1-Cre;tdTomato mice (iPSC Wnt1 ) were employed to lineage-trace Isl1 + CPCs. Results: Temporal analysis of Isl1-nLacZ embryos illustrated a transient, stage-specific reporter gene activity in mesendodermal and neuroectodermal cells. Particularly, at embryonic day (E)9.5, reporter gene activity (x-gal), was strong in the outflow tract (OFT), and exhibited a weak, spotty pattern in the heart. At E12.5, x-gal was strong in the neural tube (NT); reduced in the OFT; and undetectable in the heart. Isl1 immunohistochemistry (IHC) illustrated similar activity of x-gal with endogenous Isl1 expression. Importantly, x-gal remained permanently undetected in the heart. Isl1 IHC in E12.5 Wnt1-Cre;tdTomato and Wnt1::FlpE;RC::Fela embryos indicated that Isl1 + cells in the OFT and NT colocalized with Wnt1 reporter transgenes. At E18.5 and postnatal day 1 (PN1), Isl1 + cells were exclusively of Wnt1 lineage, indicating that Isl1 + CPCs are CNC- and not SHF-derived. Since CNCs minimally contribute cardiomyocytes in mammals, a presumptive full cardiomyogenic capacity of Isl1 + CPCs potentially contrasts with a CNC origin. To address this controversy, we differentiated iPSC Wnt1 toward the CNC lineage, using a previously established embryoid body (EB) differentiation protocol involving transient BMP antagonism. At ~EB-day 9, tdTomato + /Isl1 + CNCs emerged, which progressively differentiated into spontaneously beating, Nkx2.5 + cardiomyocytes. Conclusions: Our findings clarify that Isl1 + CPCs are of CNC and not SHF origin, and suggest a novel role of the mammalian CNC, as a contributor of long-lived myocardial progenitors that could be targeted for heart-related therapeutic purposes.

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Spotlight on Isl1: A Key Player in Cardiovascular Development and Diseases

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.793605 ◽

2021 ◽

Vol 9 ◽

Author(s):

Jie Ren ◽

Danxiu Miao ◽

Yanshu Li ◽

Rui Gao

Keyword(s):

Transcription Factor ◽

Regulatory Network ◽

Molecular Basis ◽

Marker Gene ◽

Cardiovascular Development ◽

Second Heart Field ◽

Multiple Organs ◽

Heart Field ◽

And Function ◽

Cardiac Transcription Factors

Cardiac transcription factors orchestrate a regulatory network controlling cardiovascular development. Isl1, a LIM-homeodomain transcription factor, acts as a key player in multiple organs during embryonic development. Its crucial roles in cardiovascular development have been elucidated by extensive studies, especially as a marker gene for the second heart field progenitors. Here, we summarize the roles of Isl1 in cardiovascular development and function, and outline its cellular and molecular modes of action, thus providing insights for the molecular basis of cardiovascular diseases.

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Genetic and Cellular Interaction During Cardiovascular Development Implicated in Congenital Heart Diseases

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.653244 ◽

2021 ◽

Vol 8 ◽

Author(s):

Kazuki Kodo ◽

Keiko Uchida ◽

Hiroyuki Yamagishi

Keyword(s):

Neural Crest ◽

Congenital Heart ◽

Cellular Interaction ◽

Cardiovascular Development ◽

Cardiac Neural Crest ◽

Second Heart Field ◽

Genomic Architecture ◽

Heart Field ◽

First Heart Field ◽

Mutation Analyses

Congenital heart disease (CHD) is the most common life-threatening congenital anomaly. CHD occurs due to defects in cardiovascular development, and the majority of CHDs are caused by a multifactorial inheritance mechanism, which refers to the interaction between genetic and environmental factors. During embryogenesis, the cardiovascular system is derived from at least four distinct cell lineages: the first heart field, second heart field, cardiac neural crest, and proepicardial organ. Understanding the genes involved in each lineage is essential to uncover the genomic architecture of CHD. Therefore, we provide an overview of recent research progress using animal models and mutation analyses to better understand the molecular mechanisms and pathways linking cardiovascular development and CHD. For example, we highlight our recent work on genes encoding three isoforms of inositol 1,4,5-trisphosphate receptors (IP3R1, 2, and 3) that regulate various vital and developmental processes, which have genetic redundancy during cardiovascular development. Specifically, IP3R1 and 2 have redundant roles in the atrioventricular cushion derived from the first heart field lineage, whereas IP3R1 and 3 exhibit redundancy in the right ventricle and the outflow tract derived from the second heart field lineage, respectively. Moreover, 22q11.2 deletion syndrome (22q11DS) is highly associated with CHD involving the outflow tract, characterized by defects of the cardiac neural crest lineage. However, our studies have shown that TBX1, a major genetic determinant of 22q11DS, was not expressed in the cardiac neural crest but rather in the second heart field, suggesting the importance of the cellular interaction between the cardiac neural crest and the second heart field. Comprehensive genetic analysis using the Japanese genome bank of CHD and mouse models revealed that a molecular regulatory network involving GATA6, FOXC1/2, TBX1, SEMA3C, and FGF8 was essential for reciprocal signaling between the cardiac neural crest and the second heart field during cardiovascular development. Elucidation of the genomic architecture of CHD using induced pluripotent stem cells and next-generation sequencing technology, in addition to genetically modified animal models and human mutation analyses, would facilitate the development of regenerative medicine and/or preventive medicine for CHD in the near future.

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The Impact of Spaceflight and Microgravity on the Human Islet-1+ Cardiovascular Progenitor Cell Transcriptome

International Journal of Molecular Sciences ◽

10.3390/ijms22073577 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3577

Author(s):

Victor Camberos ◽

Jonathan Baio ◽

Ana Mandujano ◽

Aida F. Martinez ◽

Leonard Bailey ◽

...

Keyword(s):

Early Stage ◽

Space Station ◽

Cardiovascular Development ◽

Support Cell ◽

Cell Transcriptome ◽

Islet 1 ◽

Life On Earth ◽

The Impact ◽

And Oxidative Stress ◽

Insight Into

Understanding the transcriptomic impact of microgravity and the spaceflight environment is relevant for future missions in space and microgravity-based applications designed to benefit life on Earth. Here, we investigated the transcriptome of adult and neonatal cardiovascular progenitors following culture aboard the International Space Station for 30 days and compared it to the transcriptome of clonally identical cells cultured on Earth. Cardiovascular progenitors acquire a gene expression profile representative of an early-stage, dedifferentiated, stem-like state, regardless of age. Signaling pathways that support cell proliferation and survival were induced by spaceflight along with transcripts related to cell cycle re-entry, cardiovascular development, and oxidative stress. These findings contribute new insight into the multifaceted influence of reduced gravitational environments.

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Lamb1a regulates atrial growth by limiting excessive, contractility-dependent second heart field addition during zebrafish heart development

10.1101/2021.03.10.434727 ◽

2021 ◽

Author(s):

Christopher J. Derrick ◽

Eric J. G. Pollitt ◽

Ashley Sanchez Sevilla Uruchurtu ◽

Farah Hussein ◽

Emily S. Noёl

Keyword(s):

Heart Development ◽

Cardiac Development ◽

Basement Membranes ◽

Atrioventricular Canal ◽

Cardiac Morphogenesis ◽

Heart Morphogenesis ◽

Second Heart Field ◽

Heart Field ◽

Heart Size ◽

Zebrafish Heart

AbstractDuring early vertebrate heart development, the heart transitions from a linear tube to a complex asymmetric structure. This process includes looping of the tube and ballooning of the emerging cardiac chambers, which occur simultaneously with growth of the heart. A key driver of cardiac growth is deployment of cells from the Second Heart Field (SHF) into both poles of the heart, with cardiac morphogenesis and growth intimately linked in heart development. Laminin is a core component of extracellular matrix (ECM) basement membranes, and although mutations in specific laminin subunits are linked with a variety of cardiac abnormalities, including congenital heart disease and dilated cardiomyopathy, no role for laminin has been identified in early vertebrate heart morphogenesis. We identified dynamic, tissue-specific expression of laminin subunit genes in the developing zebrafish heart, supporting a role for laminins in heart morphogenesis.lamb1amutants exhibit cardiomegaly from 2dpf onwards, with subsequent progressive defects in cardiac morphogenesis characterised by a failure of the chambers to compact around the developing atrioventricular canal. We show that loss oflamb1aresults in excess addition of SHF cells to the atrium, revealing that Lamb1a functions to limit heart size during cardiac development by restricting SHF addition to the venous pole.lamb1amutants exhibit hallmarks of altered haemodynamics, and specifically blocking cardiac contractility inlamb1amutants rescues heart size and atrial SHF addition. Furthermore, we identify that FGF and RA signalling, two conserved pathways promoting SHF addition, are regulated by heart contractility and are dysregulated inlamb1amutants, suggesting that laminin mediates interactions between SHF deployment, heart biomechanics, and biochemical signalling during heart development. Together, this describes the first requirement for laminins in early vertebrate heart morphogenesis, reinforcing the importance of specialised ECM composition in cardiac development.

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