scholarly journals Mechanisms and Insights for the Development of Heart Failure Associated with Cancer Therapy

Children ◽  
2021 ◽  
Vol 8 (9) ◽  
pp. 829
Author(s):  
Claire Fraley ◽  
Sarah A. Milgrom ◽  
Lavanya Kondapalli ◽  
Matthew R. G. Taylor ◽  
Luisa Mestroni ◽  
...  
Keyword(s):  
Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Childhood Cancer Survivors ◽  
Cardiovascular Complications ◽  
Cancer Therapies ◽  
Hematopoietic Stem ◽  
Targeted Cancer Therapies ◽  
Underlying Mechanisms ◽  
Induced Pluripotent

Cardiotoxicity is a well-recognized late effect among childhood cancer survivors. With various pediatric cancers becoming increasingly curable, it is imperative to understand the disease burdens that survivors may face in the future. In order to prevent or mitigate cardiovascular complications, we must first understand the mechanistic underpinnings. This review will examine the underlying mechanisms of cardiotoxicity that arise from traditional antineoplastic chemotherapies, radiation therapy, hematopoietic stem cell transplantation, as well as newer cellular therapies and targeted cancer therapies. We will then propose areas for prevention, primarily drawing from the anthracycline-induced cardiotoxicity literature. Finally, we will explore the role of human induced pluripotent stem cell cardiomyocytes and genetics in advancing the field of cardio-oncology.

scholarly journals Tyrosyl-tRNA synthetase stimulates thrombopoietin-independent hematopoiesis accelerating recovery from thrombocytopenia

2018 ◽  
Vol 115 (35) ◽  
pp. E8228-E8235 ◽  
Author(s):  
Taisuke Kanaji ◽  
My-Nuong Vo ◽  
Sachiko Kanaji ◽  
Alessandro Zarpellon ◽  
Ryan Shapiro ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Formation ◽  
Induced Pluripotent Stem Cell ◽  
Trna Synthetase ◽  
Monocytic Cells ◽  
Formation Continue ◽  
Hematopoietic Stem ◽  
Culture Production ◽  
High Ploidy ◽  
Induced Pluripotent

New mechanisms behind blood cell formation continue to be uncovered, with therapeutic approaches for hematological diseases being of great interest. Here we report an enzyme in protein synthesis, known for cell-based activities beyond translation, is a factor inducing megakaryocyte-biased hematopoiesis, most likely under stress conditions. We show an activated form of tyrosyl-tRNA synthetase (YRSACT), prepared either by rationally designed mutagenesis or alternative splicing, induces expansion of a previously unrecognized high-ploidy Sca-1+ megakaryocyte population capable of accelerating platelet replenishment after depletion. Moreover, YRSACT targets monocytic cells to induce secretion of transacting cytokines that enhance megakaryocyte expansion stimulating the Toll-like receptor/MyD88 pathway. Platelet replenishment by YRSACT is independent of thrombopoietin (TPO), as evidenced by expansion of the megakaryocytes from induced pluripotent stem cell-derived hematopoietic stem cells from a patient deficient in TPO signaling. We suggest megakaryocyte-biased hematopoiesis induced by YRSACT offers new approaches for treating thrombocytopenia, boosting yields from cell-culture production of platelet concentrates for transfusion, and bridging therapy for hematopoietic stem cell transplantation.

Role of Mcl-1 in regulation of cell death in human induced pluripotent stem cell-derived cardiomyocytes in vitro

2018 ◽  
Vol 360 ◽  
pp. 88-98 ◽  
Author(s):  
Liang Guo ◽  
Sandy Eldridge ◽  
Michael Furniss ◽  
Jodie Mussio ◽  
Myrtle Davis
Keyword(s):  
Cell Death ◽  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Induced Pluripotent

scholarly journals Personalized medicine in cardio-oncology: the role of induced pluripotent stem cell

2019 ◽  
Vol 115 (5) ◽  
pp. 949-959 ◽  
Author(s):  
Nazish Sayed ◽  
Mohamed Ameen ◽  
Joseph C Wu
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Association Studies ◽  
Induced Pluripotent Stem Cell ◽  
Human Diseases ◽  
Genome Wide Association Studies ◽  
Genomic Variants ◽  
Induced Pluripotent

Abstract Treatment of cancer has evolved in the last decade with the introduction of new therapies. Despite these successes, the lingering cardiotoxic side-effects from chemotherapy remain a major cause of morbidity and mortality in cancer survivors. These effects can develop acutely during treatment, or even years later. Although many risk factors can be identified prior to beginning therapy, unexpected toxicity still occurs, often with lasting consequences. Specifically, cardiotoxicity results in cardiac cell death, eventually leading to cardiomyopathy and heart failure. Certain risk factors may predispose an individual to experiencing adverse cardiovascular effects, and when unexpected cardiotoxicity occurs, it is generally managed with supportive care. Animal models of chemotherapy-induced cardiotoxicity have provided some mechanistic insights, but the precise mechanisms by which these drugs affect the heart remains unknown. Moreover, the genetic rationale as to why some patients are more susceptible to developing cardiotoxicity has yet to be determined. Many genome-wide association studies have identified genomic variants that could be associated with chemotherapy-induced cardiotoxicity, but the lack of validation has made these studies more speculative rather than definitive. With the advent of human induced pluripotent stem cell (iPSC) technology, researchers not only have the opportunity to model human diseases, but also to screen drugs for their efficacy and toxicity using human cell models. Furthermore, it allows us to conduct validation studies to confirm the role of genomic variants in human diseases. In this review, we discuss the role of iPSCs in modelling chemotherapy-induced cardiotoxicity.

scholarly journals 3213 Unraveling the role of Phospholamban (PLN) in humans via the characterization of Induced Pluripotent Stem Cell (iPSC) Cardiomyocytes (CM) derived from carriers of a lethal PLN mutation

2019 ◽  
Vol 3 (s1) ◽  
pp. 26-26
Author(s):  
Maria Giovanna Trivieri ◽  
Francesca Stillitano ◽  
Delaine Ceholski ◽  
Irene Turnbull ◽  
Kevin Costa ◽  
...  
Keyword(s):  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
State Of The Art ◽  
Induced Pluripotent Stem Cell ◽  
Relevant Model ◽  
Study Population ◽  
Induced Pluripotent ◽  
Ca Homeostasis

OBJECTIVES/SPECIFIC AIMS: To study the biology of Phosholamban (PLN) in a human relevant model. METHODS/STUDY POPULATION: State of the art stem-cell technologies using iPSC-CMs derived from carriers of a lethal PLN mutation. RESULTS/ANTICIPATED RESULTS: Our preliminary data demonstrate that this particular PLN mutation (L39) results in reduced expression and mis-localization of PLN as well as increased incidence of early after depolarization in isolated iPSC-CMs. DISCUSSION/SIGNIFICANCE OF IMPACT: Phospholamban (PLN) is a critical regulator of Ca++ homeostasis yet many uncertainties still remain regarding its role in humans. Our study will provide unique insights into the pathophysiology of this protein in HF.

scholarly journals Highly efficient SARS-CoV-2 infection of human cardiomyocytes: spike protein-mediated cell fusion and its inhibition

2021 ◽  
Author(s):  
Chanakha K. Navaratnarajah ◽  
David R. Pease ◽  
Peter Halfmann ◽  
Biruhalem Taye ◽  
Alison Barkhymer ◽  
...  
Keyword(s):  
Stem Cell ◽  
Amino Acid ◽  
Pluripotent Stem Cell ◽  
Cardiac Tissue ◽  
Induced Pluripotent Stem Cell ◽  
Cardiovascular Complications ◽  
Spike Protein ◽  
Single Amino Acid ◽  
Cardiac Damage ◽  
Induced Pluripotent

Severe cardiovascular complications can occur in coronavirus disease of 2019 (COVID-19) patients. Cardiac damage is attributed mostly to the aberrant host response to acute respiratory infection. However, direct infection of cardiac tissue by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) also occurs. We examined here the cardiac tropism of SARS-CoV-2 in spontaneously beating human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). These cardiomyocytes express the angiotensin-converting enzyme 2 (ACE2) receptor but not the transmembrane protease serine 2 (TMPRSS2) that mediates spike protein cleavage in the lungs. Nevertheless, SARS-CoV-2 infection of hiPSC-CMs was prolific: viral transcripts accounted for about 88% of total mRNA. In the cytoplasm of infected hiPSC-CMs, smooth walled exocytic vesicles contained numerous 65-90 nm particles with canonical ribonucleocapsid structures, and virus-like particles with knob-like spikes covered the cell surface. To better understand how SARS-CoV-2 spreads in hiPSC-CMs we engineered an expression vector coding for the spike protein with a monomeric emerald-green fluorescent protein fused to its cytoplasmic tail (S-mEm). Proteolytic processing of S-mEm and the parental spike were equivalent. Live cell imaging tracked spread of S-mEm cell-to-cell and documented formation of syncytia. A cell-permeable, peptide-based molecule that blocks the catalytic site of furin and furin-like proteases abolished cell fusion. A spike mutant with the single amino acid change R682S that disrupts the multibasic furin cleavage motif was fusion inactive. Thus, SARS-CoV-2 replicates efficiently in hiPSC-CMs and furin and/or furin-like-protease activation of its spike protein is required for fusion-based cytopathology. This hiPSC-CM platform enables target-based drug discovery in cardiac COVID-19. Importance Cardiac complications frequently observed in COVID-19 patients are tentatively attributed to systemic inflammation and thrombosis, but viral replication has occasionally been confirmed in cardiac tissue autopsy materials. We developed an in vitro model of SARS-CoV-2 spread in myocardium using induced pluripotent stem cell-derived cardiomyocytes. In these highly differentiated cells, viral transcription levels exceeded those previously documented in permissive transformed cell lines. To better understand the mechanisms of SARS-CoV-2 spread, we expressed a fluorescent version of its spike protein that allowed us to characterize a fusion-based cytopathic effect. A mutant of the spike protein with a single amino acid mutation in the furin/furin-like protease cleavage site lost cytopathic function. Of note, the fusion activities of the spike protein of other coronaviruses correlated with the level of cardiovascular complications observed in infections with the respective viruses. These data indicate that SARS-CoV-2 may cause cardiac damage by fusing cardiomyocytes.

A PRC2-Dependent Repressive Role of PRDM14 in Human Embryonic Stem Cells and Induced Pluripotent Stem Cell Reprogramming

Stem Cells ◽  
2013 ◽  
Vol 31 (4) ◽  
pp. 682-692 ◽  
Author(s):  
Yun-Shen Chan ◽  
Jonathan Göke ◽  
Xinyi Lu ◽  
Nandini Venkatesan ◽  
Bo Feng ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Embryonic Stem Cells ◽  
Human Embryonic Stem Cells ◽  
Pluripotent Stem Cell ◽  
Embryonic Stem ◽  
Induced Pluripotent Stem Cell ◽  
Cell Reprogramming ◽  
Induced Pluripotent
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