ErbB2 promotes endothelial phenotype of human left ventricular epicardial highly proliferative cells (eHiPC)

Ryzhov, Sergey; Robich, Michael P.; Roberts, Daniel J.; Favreau-Lessard, Amanda J.; Peterson, Sarah; Jachimowicz, Edward; Rath, Rutwik; Vary, Calvin P.H.; Quinn, Reed D.; Kramer, Robert S.; Sawyer, Douglas B.

doi:10.1016/j.yjmcc.2017.12.013

Cited by 6 publications

(9 citation statements)

References 63 publications

(68 reference statements)

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“…Transcriptomic analysis of bona fide iPSC-ECs on the final day of differentiation identified four distinct populations of iPSC-ECs, noted by enriched expressions of CLDN5, APLNR, GJA5, and ESM1 respectively. Regulation of various signaling pathways controls biological and physiological functionality of endothelial cells 36,37 . Likewise, the identified iPSC-EC subpopulations displayed enriched expression of genes that together indicate specialized biological functions as metabolically active (CLDN5+), immune-responsive (APLNR+), arterial (GJA5+), and activated (ESM1+) ECs.…”

Section: Discussionmentioning

confidence: 99%

Large-Scale Single-Cell RNA-Seq Reveals Molecular Signatures of Heterogeneous Populations of Human Induced Pluripotent Stem Cell-Derived Endothelial Cells

Paik

Tian

Lee

et al. 2018

Circulation Research

120

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Massively parallel, droplet-based scRNA-seq allowed meticulous analysis of thousands of human iPSCs subjected to iPSC-EC differentiation. Results showed inefficiency of the differentiation technique, which can be improved with further studies based on identification of molecular signatures that inhibit expansion of nonendothelial cell types. Subtypes of bona fide human iPSC-ECs were also identified, allowing us to sort for iPSC-ECs with specific biological function and identity.

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Section: Discussionmentioning

confidence: 99%

Large-Scale Single-Cell RNA-Seq Reveals Molecular Signatures of Heterogeneous Populations of Human Induced Pluripotent Stem Cell-Derived Endothelial Cells

Paik

Tian

Lee

et al. 2018

Circulation Research

120

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“…With this study identifying a model of vascular toxicity instead of cardiac myocyte toxicity, we have a model to further test the efficiency of cell-based therapies to restore endothelial cell number and vascular function. Our group has previously isolated highly proliferative cells from epicardial left ventricular biopsies (eHiPCs) in patients undergoing coronary artery bypass grafting surgery [23]. We identified a subset of these eHiPCs that exhibit endothelial-like properties and are currently undergoing further characterization to determine their potential for revascularization.…”

Section: Systemic Effects Vs Cardiac Effectsdosing Considerationsmentioning

confidence: 99%

Systemic and cardiac susceptibility of immune compromised mice to doxorubicin

Favreau-Lessard¹,

Blaszyk²,

Jones³

et al. 2019

Cardio-Oncology

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Background: Anthracycline chemotherapy is an effective and widely used treatment for solid tumors and hematological malignancies regardless of its known cardiotoxicity. The mechanisms of the cardiotoxicity are not fully understood and methods to protect the heart during or following anthracycline chemotherapy are currently unclear. In order to examine the efficacy of human cell based therapy in anthracycline-induced injury, we characterized a mouse model using an immune compromised strain of mice capable of accepting human cells.Methods: Immune compromised mice (NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ) were repeatedly exposed to pharmaceutical grade doxorubicin (0.5 mg/kg -4 mg/kg). Cardiotoxicity was assessed by echocardiography and μCT imaging of the coronary vascular bed as well as by flow cytometry and by histological assessments of anthracycline-induced cardiac tissue damage. Results: The immune compromised mice were highly susceptible to doxorubicin treatment. Doxorubicin induced both systemic and cardiac toxicities. Gastrointestinal and hepatic injury occurred at 4 mg/kg and 1.5 mg/kg dosing while mice receiving 0.5 mg/kg weekly only displayed hepatic damage. Repeated exposure to 0.5 mg/kg anthracyclines resulted in cardiac toxicity. Flow cytometric analysis of hearts indicated a loss in endothelial and cardiac progenitor cells after doxorubicin treatment. This endothelial loss is corroborated by the lack of small vessels detected by μCT in the hearts of mice exposed to doxorubicin. Histological assessment shows no overt cardiomyocyte injury but livers from mice treated with doxorubicin show marked hepatic plate atrophy with intracytoplasmic and canalicular cholestasis, rare pericentral hepatocellular necrosis and significant zone 3 iron accumulation, likely an indication of metabolic injury due to doxorubicin toxicity. Conclusions: Immune compromised mice are sensitive to doxorubicin therapy resulting in systemic complications in addition to cardiovascular toxicity. Anthracycline-induced cardiotoxicity is observed at very low doses in NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ mice.

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“…NRG-1 can also regulate angiogenesis via the prevention of apoptosis of endothelial progenitor cells [ 109 ]. We have recently demonstrated that human cardiac highly proliferative cells are characterized by the expression of all four ErbB receptors [ 110 ]. These cells are characterized by high proliferative activity in vitro , and have been shown to possess progenitor properties.…”

Section: Neuregulin In Repair Of Systolic Heart Failurementioning

confidence: 99%

Neuregulins: protective and reparative growth factors in multiple forms of cardiovascular disease

2020

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Neuregulins (NRGs) are protein ligands that act through ErbB receptor tyrosine kinases to regulate tissue morphogenesis, plasticity, and adaptive responses to physiologic needs in multiple tissues, including the heart and circulatory system. The role of NRG/ErbB signaling in cardiovascular biology, and how it responds to physiologic and pathologic stresses is a rapidly evolving field. While initial concepts focused on the role that NRG may play in regulating cardiac myocyte responses, including cell survival, growth, adaptation to stress, and proliferation, emerging data support a broader role for NRGs in the regulation of metabolism, inflammation, and fibrosis in response to injury. The constellation of effects modulated by NRGs may account for the findings that two distinct forms of recombinant NRG-1 have beneficial effects on cardiac function in humans with systolic heart failure. NRG-4 has recently emerged as an adipokine with similar potential to regulate cardiovascular responses to inflammation and injury. Beyond systolic heart failure, NRGs appear to have beneficial effects in diastolic heart failure, prevention of atherosclerosis, preventing adverse effects on diabetes on the heart and vasculature, including atherosclerosis, as well as the cardiac dysfunction associated with sepsis. Collectively, this literature supports the further examination of how this developmentally critical signaling system functions and how it might be leveraged to treat cardiovascular disease.

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ErbB2 promotes endothelial phenotype of human left ventricular epicardial highly proliferative cells (eHiPC)

Cited by 6 publications

References 63 publications

Large-Scale Single-Cell RNA-Seq Reveals Molecular Signatures of Heterogeneous Populations of Human Induced Pluripotent Stem Cell-Derived Endothelial Cells

Large-Scale Single-Cell RNA-Seq Reveals Molecular Signatures of Heterogeneous Populations of Human Induced Pluripotent Stem Cell-Derived Endothelial Cells

Systemic and cardiac susceptibility of immune compromised mice to doxorubicin

Neuregulins: protective and reparative growth factors in multiple forms of cardiovascular disease

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