SNTA1-deficient human cardiomyocytes demonstrate hypertrophic phenotype and calcium handling disorder

Background [alpha]-1-syntrophin (SNTA1), a protein encoded by SNTA1, is highly expressed in human cardiomyocytes. Mutations in SNTA1 are associated with arrhythmia and cardiomyopathy. Previous research on SNTA1 has been based on non-human cardiomyocytes. This study was designed to identify the pheno...

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Published in:Stem cell research & therapy 2022-06, Vol.13 (1), p.1-288, Article 288
Main Authors: Dong, Tao, Zhao, Yan, Jin, Hai-Feng, Shen, Lei, Lin, Yan, Si, Long-Long, Chen, Li, Liu, Ji-Cheng
Format: Article
Language:English
Subjects:
Amino acids
Analysis
Antibodies
Arrhythmia
Caffeine
Calcium (reticular)
Calcium homeostasis
Cardiac muscle
Cardiomyocytes
Cardiomyopathy
Cell differentiation
Codon
CRISPR
CRISPR-Cas9
Embryonic stem cells
Etiology
Gene expression
Genetic aspects
Genotype & phenotype
Heart cells
Homeostasis
Human embryonic stem cell
Muscle contraction
Pathogenesis
Phenotypes
Pluripotency
Proteins
Sarcoplasmic reticulum
SNTA1-deficient cardiomyocyte
Stem cells
Stop codon
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Summary:Background [alpha]-1-syntrophin (SNTA1), a protein encoded by SNTA1, is highly expressed in human cardiomyocytes. Mutations in SNTA1 are associated with arrhythmia and cardiomyopathy. Previous research on SNTA1 has been based on non-human cardiomyocytes. This study was designed to identify the phenotype of SNTA1-deficiency using human cardiomyocytes. Methods SNTA1 was knocked out in the H9 embryonic stem cell line using the CRISPR-Cas9 system. H9SNTA1KO cells were then induced to differentiate into cardiomyocytes using small molecule inhibitors. The phenotypic discrepancies associated with SNTA1-deficient cardiomyocytes were investigated. Results SNTA1 was truncated at the 149th amino acid position of PH1 domain by a stop codon (TGA) using the CRISPR-Cas9 system. SNTA1-deficiency did not affect the pluripotency of H9SNTA1KO, and they retain their in vitro ability to differentiate into cardiomyocytes. However, H9SNTA1KO derived cardiomyocytes exhibited hypertrophic phenotype, lower cardiac contractility, weak calcium transient intensity, and lower level of calcium in the sarcoplasmic reticulum. Early treatment of SNTA1-deficient cardiomyocytes with ranolazine improved the calcium transient intensity and cardiac contractility. Conclusion SNTA1-deficient cardiomyocytes can be used to research the etiology, pathogenesis, and potential therapies for myocardial diseases. The SNTA1-deficient cardiomyocyte model suggests that the maintenance of cardiac calcium homeostasis is a key target in the treatment of myocardial-related diseases. Keywords: Human embryonic stem cell, SNTA1-deficient cardiomyocyte, CRISPR-Cas9, Calcium homeostasis
ISSN:1757-6512
1757-6512
DOI:10.1186/s13287-022-02955-4