Publications by authors named "Kristy Red-Horse"

Blood vessels permeate all organs and execute myriad roles in health and disease. Here, we present a protocol to efficiently generate human artery and vein endothelial cells (ECs) from pluripotent stem cells within 3-4 days of differentiation. We delineate how to seed human pluripotent stem cells and sequentially differentiate them into primitive streak, lateral mesoderm, and either artery or vein ECs.

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The vasculature of the skeletal system is crucial for bone formation, homoeostasis and fracture repair, yet the diversity and specialization of bone-associated vessels remain poorly understood. Here we identify a specialized type of post-arterial capillary, termed type R, involved in bone remodelling. Type R capillaries emerge during adolescence around trabecular bone, possess a distinct morphology and molecular profile, and are associated with osteoprogenitors and bone-resorbing osteoclasts.

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Article Synopsis
  • COVID-19 is linked to serious thrombotic events and neurological symptoms that can persist in long COVID patients, but the mechanisms behind these complications are not well understood and treatment options are limited.
  • *Fibrinogen, a key component of blood clots, is found in high amounts in the lungs and brains of COVID-19 patients, where it correlates with the severity of the disease and can predict cognitive issues afterward.
  • *Research shows that fibrin interacts with the SARS-CoV-2 spike protein, causing inflammatory blood clots that contribute to complications like inflammation and nerve damage, suggesting that therapies targeting fibrin may be beneficial for treating both acute and long COVID cases.*
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  • Cell segregation helps organize cells during development, particularly in the formation of blood vessels, influenced by local molecular signals and mechanical forces.
  • In the retina, endothelial tip cells play a crucial role in forming arteries, with research showing that the interaction between ephrin-B2 and its receptor EphB4 is vital for determining arterial cell identity and organization.
  • Elevated ephrin-B2 activity, after losing EphB4, enhances several signaling pathways critical for vascular development and may help explain vascular issues linked to EPHB4 gene mutations in humans.
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The developmental origin of blood-forming hematopoietic stem cells (HSCs) is a longstanding question. Here, our non-invasive genetic lineage tracing in mouse embryos pinpoints that artery endothelial cells generate HSCs. Arteries are transiently competent to generate HSCs for 2.

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  • The study investigates the branching pattern of coronary arteries in humans, known as coronary dominance, and aims to understand its genetic regulation, which has been poorly understood due to challenges in studying human heart development.
  • By analyzing data from 61,043 participants in the VA Million Veteran Program, researchers identified a moderate heritability of 27.7% for coronary dominance and discovered ten significant genetic loci, particularly near a chemokine-related region.
  • The findings suggest that the gene in question plays a crucial role in the development of coronary artery patterns, as experiments in mice showed altered artery development when this gene was reduced, indicating potential targets for future medical treatments related to coronary artery conditions.
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The cardiac endothelium influences ventricular chamber development by coordinating trabeculation and compaction. However, the endothelial-specific molecular mechanisms mediating this coordination are not fully understood. Here, we identify the Sox7 transcription factor as a critical cue instructing cardiac endothelium identity during ventricular chamber development.

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Background: Collateral arteries act as natural bypasses which reroute blood flow to ischemic regions and facilitate tissue regeneration. In an injured heart, neonatal artery endothelial cells orchestrate a systematic series of cellular events, which includes their outward migration, proliferation, and coalescence into fully functional collateral arteries. This process, called artery reassembly, aids complete cardiac regeneration in neonatal hearts but is absent in adults.

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Article Synopsis
  • Collateral arteries serve as natural bypasses that maintain blood flow during artery blockages, and enhancing their development could be a potential treatment for cardiac ischemia.
  • Research using imaging and modeling on neonate and adult mouse hearts revealed that neonate collaterals are more effective at restoring blood flow compared to those in adults.
  • In adults, the growth of coronary arteries involved adding branches rather than increasing size, leading to reduced effectiveness, highlighting the difference in collateral artery functionality between fetal and adult hearts and emphasizing their importance for heart regeneration and therapeutic strategies.
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Outflow tract (OFT) develops from cardiac progenitor cells in the second heart field (SHF) domain. APJ, a G-Protein Coupled Receptor, is expressed by cardiac progenitors in the SHF. By lineage tracing APJ+SHF cells, we show that these cardiac progenitors contribute to the cells of OFT, which eventually give rise to aorta and pulmonary trunk/artery upon its morphogenesis.

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Immunoglobulin family and carbohydrate vascular addressins encoded by Madcam1 and St6gal1 control lymphocyte homing into intestinal tissues, regulating immunity and inflammation. The addressins are developmentally programmed to decorate endothelial cells lining gut post-capillary and high endothelial venules (HEV), providing a prototypical example of organ- and segment-specific endothelial specialization. We identify conserved NKX-COUP-TFII composite elements (NCCE) in regulatory regions of Madcam1 and St6gal1 that bind intestinal homeodomain protein NKX2-3 cooperatively with venous nuclear receptor COUP-TFII to activate transcription.

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Metastasis is responsible for most breast cancer-related deaths; however, identifying the cellular determinants of metastasis has remained challenging. Here, we identified a minority population of immature / tumor epithelial cells in human breast tumor biopsies that display angiogenic features and are marked by the expression of the oncogene, . Higher abundance of basal cells correlated with tumor endothelial content and predicted poor distant recurrence-free survival in patients.

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Endocardial cells lining the heart lumen are coronary vessel progenitors during embryogenesis. Re-igniting this developmental process in adults could regenerate blood vessels lost during cardiac injury, but this requires additional knowledge of molecular mechanisms. Here, we use mouse genetics and scRNA-seq to identify regulators of endocardial angiogenesis and precisely assess the role of CXCL12/CXCR4 signaling.

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Vascular endothelial cells form the inner layer of blood vessels where they have a key role in the development and maintenance of the functional circulatory system and provide paracrine support to surrounding non-vascular cells. Technical advances in the past 5 years in single-cell genomics and in in vivo genetic labelling have facilitated greater insights into endothelial cell development, plasticity and heterogeneity. These advances have also contributed to a new understanding of the timing of endothelial cell subtype differentiation and its relationship to the cell cycle.

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The mammalian neonatal heart can regenerate for 1 week after birth, after which, the majority of cardiomyocytes exit the cell cycle. Recent studies demonstrated that calcineurin mediates cell-cycle arrest of postnatal cardiomyocytes, partly through induction of nuclear translocation of the transcription factor Hoxb13 (a cofactor of Meis1). Here we show that inducible cardiomyocyte-specific deletion of calcineurin B1 in adult cardiomyocytes markedly decreases cardiomyocyte size and promotes mitotic entry, resulting in increased total cardiomyocyte number and improved left ventricular (LV) systolic function after myocardial infarction (MI).

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Stem cell research endeavors to generate specific subtypes of classically defined "cell types." Here, we generate >90% pure human artery or vein endothelial cells from pluripotent stem cells within 3-4 days. We specified artery cells by inhibiting vein-specifying signals and vice versa.

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Molecular characterization of cell types using single-cell transcriptome sequencing is revolutionizing cell biology and enabling new insights into the physiology of human organs. We created a human reference atlas comprising nearly 500,000 cells from 24 different tissues and organs, many from the same donor. This atlas enabled molecular characterization of more than 400 cell types, their distribution across tissues, and tissue-specific variation in gene expression.

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Most cell fate trajectories during development follow a diverging, tree-like branching pattern, but the opposite can occur when distinct progenitors contribute to the same cell type. During this convergent differentiation, it is unknown if cells 'remember' their origins transcriptionally or whether this influences cell behavior. Most coronary blood vessels of the heart develop from two different progenitor sources-the endocardium (Endo) and sinus venosus (SV)-but whether transcriptional or functional differences related to origin are retained is unknown.

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Aims: Non-compaction cardiomyopathy is a devastating genetic disease caused by insufficient consolidation of ventricular wall muscle that can result in inadequate cardiac performance. Despite being the third most common cardiomyopathy, the mechanisms underlying the disease, including the cell types involved, are poorly understood. We have previously shown that endothelial cell-specific deletion of the chromatin remodeller gene Ino80 results in defective coronary vessel development that leads to ventricular non-compaction in embryonic mouse hearts.

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The establishment of distinct cellular identities was pivotal during the evolution of Metazoa, enabling the emergence of an array of specialized tissues with different functions. In most animals including vertebrates, cell specialization occurs in response to a combination of intrinsic (e.g.

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Endogenous capability of the post-mitotic human heart holds great promise to restore the injured myocardium. Recent evidence indicates that the extracellular vesicles (EVs) regulate cardiac homeostasis and regeneration. Here, we investigated the molecular mechanism of EVs for self-repair.

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Purpose Of Review: There have been tremendous advances in the tools available for surveying blood vessels within whole organs and tissues. Here, we summarize some of the recent developments in methods for immunolabeling and imaging whole organs and provide a protocol optimized for the heart.

Recent Findings: Multiple protocols have been established for chemically clearing large organs and variations are compatible with cell type-specific labeling.

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Purpose Of Review: Collateral arteries create artery-artery anastomoses that could serve as natural bypasses that in the heart could relieve the various complications of ischemia heart disease. Recent work using animal models have begun to reveal details of how coronary collateral arteries form.

Recent Findings: Mouse genetics has been used to study the cellular and molecular mechanisms of collateral artery development.

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