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1.
J Extracell Vesicles ; 12(10): e12371, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37795828

RESUMEN

Small-interfering RNA (siRNA) therapy is considered a powerful therapeutic strategy for treating cardiac hypertrophy, an important risk factor for subsequent cardiac morbidity and mortality. However, the lack of safe and efficient in vivo delivery of siRNAs is a major challenge for broadening its clinical applications. Small extracellular vesicles (sEVs) are a promising delivery system for siRNAs but have limited cell/tissue-specific targeting ability. In this study, a new generation of heart-targeting sEVs (CEVs) has been developed by conjugating cardiac-targeting peptide (CTP) to human peripheral blood-derived sEVs (PB-EVs), using a simple, rapid and scalable method based on bio-orthogonal copper-free click chemistry. The experimental results show that CEVs have typical sEVs properties and excellent heart-targeting ability. Furthermore, to treat cardiac hypertrophy, CEVs are loaded with NADPH Oxidase 4 (NOX4) siRNA (siNOX4). Consequently, CEVs@siNOX4 treatment enhances the in vitro anti-hypertrophic effects by CEVs with siRNA protection and heart-targeting ability. In addition, the intravenous injection of CEVs@siNOX4 into angiotensin II (Ang II)-treated mice significantly improves cardiac function and reduces fibrosis and cardiomyocyte cross-sectional area, with limited side effects. In conclusion, the utilization of CEVs represents an efficient strategy for heart-targeted delivery of therapeutic siRNAs and holds great promise for the treatment of cardiac hypertrophy.


Asunto(s)
Vesículas Extracelulares , Ratones , Humanos , Animales , ARN Interferente Pequeño/análisis , ARN Interferente Pequeño/genética , NADPH Oxidasa 4/genética , NADPH Oxidasa 4/análisis , Vesículas Extracelulares/química , Cardiomegalia/terapia , Cardiomegalia/prevención & control , Miocitos Cardíacos
2.
Stem Cell Res ; 65: 102940, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36260954

RESUMEN

PITX2 is a homeobox gene located in the human 4q25 locus and is commonly associated with atrial fibrillation (AF). Here, we generated two PITX2 knock-out human induced pluripotent stem cell (iPSC) lines using CRISPR/Cas9 genome editing. The edited iPSCs maintained fullpluripotency, normal karyotype and spontaneousdifferentiation capability. This cell line provides a suitable model for investigating the physiopathologyof PITX2 mutation in atrial fibrillation.


Asunto(s)
Fibrilación Atrial , Células Madre Pluripotentes Inducidas , Humanos , Sistemas CRISPR-Cas/genética
3.
Stem Cell Res ; 64: 102901, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36037555

RESUMEN

TTN mutations are the common genetic cause for various types of cardiomyopathies (e.g., dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy) and skeletal myopathies. Here, we generated three TTN knock-out human induced pluripotent stem cell (iPSC) lines using CRISPR/Cas9 system. These cell lines, which exhibit normal karyotype, typical morphology and pluripotency, could provide useful platform for investigating the role of TTN in associated disorders.


Asunto(s)
Displasia Ventricular Derecha Arritmogénica , Cardiomiopatías , Cardiomiopatía Dilatada , Células Madre Pluripotentes Inducidas , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Sistemas CRISPR-Cas/genética , Cardiomiopatía Dilatada/genética , Cardiomiopatías/metabolismo , Displasia Ventricular Derecha Arritmogénica/genética , Mutación , Conectina/genética , Conectina/metabolismo
4.
Stem Cell Res ; 63: 102878, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35917600

RESUMEN

E192K missense mutation of TPM1 has been found in different types of cardiomyopathies (e.g., hypertrophic cardiomyopathy, dilated cardiomyopathy, and left ventricular non-compaction), leading to systolic dysfunction, diastolic dysfunction, and/or tachyarrhythmias. Here, we generated a heterozygous TPM1-E192K knock-in human induced pluripotent stem cell (iPSC) line using CRISPR/Cas9-based genome editing system. The cells exhibit normal karyotype, typical stem cell morphology, expression of pluripotency markers and differentiation ability into three germ layers. Accordingly, this cell line could provide a useful cell resource for exploring the pathogenic role of TPM1-E192K mutation in different types of cardiomyopathies.


Asunto(s)
Cardiomiopatías , Células Madre Pluripotentes Inducidas , Sistemas CRISPR-Cas/genética , Cardiomiopatías/metabolismo , Edición Génica , Heterocigoto , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Mutación , Tropomiosina/genética
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