Patient and Disease–Specific Induced Pluripotent Stem Cells for Discovery of Personalized Cardiovascular Drugs and Therapeutics

Pharmacological Reviews, Journal Year: 2019, Volume and Issue: 72(1), P. 320 - 342

Published: Dec. 23, 2019

Human induced pluripotent stem cells (iPSCs) have emerged as an effective platform for regenerative therapy, disease modeling, and drug discovery. iPSCs allow the production of limitless supply patient-specific somatic that enable advancement in cardiovascular precision medicine. Over past decade, researchers developed protocols to differentiate multiple lineages, well enhance maturity functionality these cells. Despite significant advances, therapy discovery lagged behind other fields such oncology. We speculate this paucity is due a previous lack efficient, reproducible, translational model systems. Notably, existing testing platforms rely on animal studies clinical trials, but investigations models inherent limitations interspecies differences. Moreover, trials are inherently flawed by assuming all individuals with will respond identically ignoring genetic epigenomic variations define our individuality. With ever-improving differentiation phenotyping methods, iPSC-derived unprecedented opportunities discover new targets screen compounds disease. Imbued information individual, vastly improve ability test drugs efficiently, tailor titrate each patient.

Language: Английский

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Apoptotic vesicles restore liver macrophage homeostasis to counteract type 2 diabetes

Journal of Extracellular Vesicles, Journal Year: 2021, Volume and Issue: 10(7)

Published: May 1, 2021

Apoptosis is a naturally occurring process generating plenty of apoptotic vesicles (apoVs), but the feature, fate and function apoVs remain largely unknown. Notably, as an appealing source for cell therapy, mesenchymal stem cells (MSCs) undergo necessary apoptosis release during therapeutic application. In this study, we characterized used MSC-derived to treat type 2 diabetes (T2D) mice, found that were efferocytosed by macrophages functionally modulated liver macrophage homeostasis counteract T2D. We showed can induce reprogramming at transcription level in efferocytosis-dependent manner, leading inhibition accumulation transformation towards anti-inflammation phenotype T2D liver. At molecular level, discovered calreticulin (CRT) was exposed on surface act critical 'eat-me' signal mediating apoV efferocytosis regulatory effects. Importantly, demonstrated CRT-mediated contributes therapy with alleviation phenotypes including glucose intolerance insulin resistance. These findings uncover functional restores ameliorates

Language: Английский

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Mitochondrial-Targeted Therapy for Doxorubicin-Induced Cardiotoxicity

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(3), P. 1912 - 1912

Published: Feb. 9, 2022

Anthracyclines, such as doxorubicin, are effective chemotherapeutic agents for the treatment of cancer, but their clinical use is associated with severe and potentially life-threatening cardiotoxicity. Despite decades research, options remain limited. The mitochondria commonly considered to be main target doxorubicin mitochondrial dysfunction hallmark doxorubicin-induced Here, we review pathogenic mechanisms cardiotoxicity present an update on cardioprotective strategies this disorder. Specifically, focus that can protect cover different therapeutic modalities encompassing small molecules, post-transcriptional regulators, transfer. We also discuss shortcomings existing models explore advances in human pluripotent stem cell derived cardiomyocytes a platform facilitate identification novel treatments against

Language: Английский

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Apoptotic bodies for advanced drug delivery and therapy

Journal of Controlled Release, Journal Year: 2022, Volume and Issue: 351, P. 394 - 406

Published: Sept. 27, 2022

Language: Английский

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Repurposing drugs to treat cardiovascular disease in the era of precision medicine

Nature Reviews Cardiology, Journal Year: 2022, Volume and Issue: 19(11), P. 751 - 764

Published: May 23, 2022

Language: Английский

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Mir-30d Regulates Cardiac Remodeling by Intracellular and Paracrine Signaling

Circulation Research, Journal Year: 2020, Volume and Issue: 128(1)

Published: Oct. 23, 2020

Previous translational studies implicate plasma extracellular microRNA-30d (miR-30d) as a biomarker in left ventricular remodeling and clinical outcome heart failure (HF) patients, although precise mechanisms remain obscure.

Language: Английский

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MAP4K Family Kinases and DUSP Family Phosphatases in T-Cell Signaling and Systemic Lupus Erythematosus

Cells, Journal Year: 2019, Volume and Issue: 8(11), P. 1433 - 1433

Published: Nov. 13, 2019

T cells play a critical role in the pathogenesis of systemic lupus erythematosus (SLE), which is severe autoimmune disease. In past 60 years, only one new therapeutic agent with limited efficacy has been approved for SLE treatment; therefore, development early diagnostic biomarkers and targets desirable. Mitogen-activated protein kinase kinases (MAP4Ks) dual-specificity phosphatases (DUSPs) are regulators MAP kinases. Several MAP4Ks DUSPs involved T-cell signaling responses. HPK1 (MAP4K1), DUSP22 (JKAP), DUSP14 negative activation. Consistently, downregulated human patients. contrast, MAP4K3 (GLK) positive regulator T-cell-mediated immune overexpression-induced RORγt–AhR complex specifically controls interleukin 17A (IL-17A) production cells, leading to overexpressed patients, as DUSP4 DUSP23. addition, also either diseases (DUSP2, DUSP7, DUSP10, DUSP12) or activation (DUSP1, DUSP5, DUSP14). this review, we summarize that potential and/or SLE.

Language: Английский

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Modeling Cardiac Disease Mechanisms Using Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Progress, Promises and Challenges

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(12), P. 4354 - 4354

Published: June 19, 2020

Cardiovascular diseases (CVDs) are a class of disorders affecting the heart or blood vessels. Despite progress in clinical research and therapy, CVDs still represent leading cause mortality morbidity worldwide. The hallmarks cardiac include dysfunction cardiomyocyte death, inflammation, fibrosis, scar tissue, hyperplasia, hypertrophy, abnormal ventricular remodeling. loss cardiomyocytes is an irreversible process that leads to fibrosis formation, which, turn, induce failure with progressive dramatic consequences. Both genetic environmental factors pathologically contribute development CVDs, but precise causes trigger their progression largely unknown. lack reliable human model systems for such has hampered unraveling underlying molecular mechanisms cellular processes involved at initial stage during progression. Over past decade, significant scientific advances field stem cell biology have literally revolutionized study disease vitro. Remarkably, possibility generate disease-relevant types from induced pluripotent cells (iPSCs) developed into unprecedented powerful opportunity achieve long-standing ambition investigate level, uncovering mechanisms, finally translate bench discoveries potential new therapeutic strategies. This review provides update on previous current iPSC-driven cardiovascular modeling, aim underlining stem-cell biology-based approaches elucidation pathophysiology these life-threatening diseases.

Language: Английский

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Modeling Cardiovascular Diseases with hiPSC-Derived Cardiomyocytes in 2D and 3D Cultures

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(9), P. 3404 - 3404

Published: May 11, 2020

In the last decade, generation of cardiac disease models based on human-induced pluripotent stem cells (hiPSCs) has become common use, providing new opportunities to overcome lack appropriate models. Although much progress been made toward hiPSC-derived cardiomyocytes (hiPS-CMs), several lines evidence indicate that two-dimensional (2D) cell culturing presents significant limitations, including hiPS-CMs immaturity and absence interaction between different types extracellular matrix. More recently, advances in bioengineering co-culture systems have allowed three-dimensional (3D) constructs cells. Within these systems, biochemical physical stimuli influence maturation hiPS-CMs, which can show structural functional properties more similar those present adult cardiomyocytes. this review, we describe latest 2D- 3D-hiPSC technology for mechanisms investigation, drug development, therapeutic studies.

Language: Английский

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Cardiac proteomics reveals sex chromosome-dependent differences between males and females that arise prior to gonad formation

Developmental Cell, Journal Year: 2021, Volume and Issue: 56(21), P. 3019 - 3034.e7

Published: Oct. 19, 2021

Language: Английский

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