Molecular Signatures of iPSC Derived Cardiomyocytes Highlight Sex-Specific Differences

Background and Aim: Men have a higher risk of cardiovascular diseasethan women, but the molecular and physiological mechanisms remainunclear. We have previously reported the differentially expressed genesand pathways between male and female heart tissue using donor andpostmortem adult human heart samples. Here, using RNA-Seq results,we compared the transcriptome expression profile of male and femaleiPSC-derived cardiomyocytes (iPSC-CM).Methods: We compared 5 female iPSC-CM versus 11 male iPSC-CM.All iPSCs generated using Sendai virus technique and differentiated intocardiomyocytes using a small-molecule-based monolayer method. cDNAlibraries for 16 samples were generated and sequenced. We used theseRNA-Seq data that were publicly available in the NCBI GEO database.RNA-Seq analysis was performed using tuxedo pipeline.Results: RNA-Seq results indicated that 1811 genes differentiallyexpressed between male and female iPSC-CMs. We found 1114 genesupregulated in male and 700 genes upregulated in the female. From 87differentially expressed X- linked genes, 44 genes overexpressed in femaleand 43 overexpressed in the male. Fourteen Y-linked genes expressedin all-male iPSC-CMs. RNA-Seq results indicated very low expressionof pluripotency markers (Nanog, POU5F1, etc) and high expression ofcardiac marker genes (TBX5, TTN, etc) in all iPSC-CMs. Gene ontologyanalysis indicated the overexpression of cardiac contractile genes(ventricular myocyte phenotype genes and atrial myocyte phenotypegenes), adhesion molecules and calcium signaling pathway genes inmale iPSC-CMs and overexpression of Pluripotency markers and Wnt/-catenin pathway genes have been observed in female iPSC-CMs.Conclusion: The gene expression profile of iPSC-CMs reveals genderspecificdifferences. RNA expression results showed that male iPSC-CMsare more similar to differentiated cardiomyocytes and female iPSC-CMsare more similar to neonate cardiomyocytes. Due to sex differences in gene expression profile of iPSC-CMs, we recommend using both maleand female cells in all biological studies.

کلیدواژه ها:

iPSC derived cardiomyocytes ، RNA-Seq ، Differentially expressed genes ، Pluripotency