Role of somatic cell sources in the maturation degree of human induced pluripotent stem cell-derived cardiomyocytes

Background: Induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs) are a unique source of human cardiomyocytes for cardiac disease modeling. Incomplete functional maturation remains a major limitation, however. One of the determinants of iPSC-CM maturation is somatic cell origin. We therefore compared iPSC-CMs derived from different somatic cell sources. Methods: Cardiac-derived mesenchymal progenitor cells (CPCs), bone marrow-derived mesenchymal stem cells (BMCs), and human dermal fibroblasts (HDFs) from same patients were reprogrammed into iPSCs and differentiated into iPSC-CMs. Expression of cardiac-specific genes, caffeine-responsive cells, and electrophysiological properties of differentiated cells were analyzed. To assess the contribution of epigenetic memory toward differences in gene expression observed during cardiac differentiation, DNA methylation patterns were determined in the early mesodermal cardiac promoter NKX2-5 and KCNQ1, which encodes for the pore-forming a-subunit of the slow component of delayed-rectifier potassium current (I-kappa s). Results: Cardiac genes (MYH6, TNNI3, KCNQ1, KCNE1) were upregulated in CPC-vs. BMC- and HOF-iPSC-CMs. At early differentiation stages, CPC-iPSC-CMs displayed higher numbers of caffeine-responsive cells than BMC- and HDF-iPSC-CMs. The hERG1 (KV11.1) blocker, E4031, followed by the IKs blocker, JNJ303, increased extracellular field potential duration in CPC-iPSC-CMs to a greater extent than in BMC- and HDF-iPSC-CMs. The promoter region of NKX2-5 was more highly methylated in BMCs and HDFs compared to CPCs, and to a lesser extent in BMC-iPSCs compared to CPC-iPSCs. Conclusions: These results suggest that human iPSCs from cardiac somatic cell sources may display enhanced capacity toward cardiac re-differentiation compared to non-cardiac cell sources, and that epigenetic mechanisms may play a role in this regard.