Key result
Combined modulation of BMP, FGF, and RA signaling pathways during the cardiac mesoderm stage of hiPSC differentiation significantly increased the yield of sinoatrial node-like cells to 55.1% compared to 34.1% with the standard protocol.
Why the study?
Biological pacemakers derived from pluripotent stem cells are a potential surrogate for sick sinus syndrome, making efficient strategies for sinoatrial node-like cell enrichment essential.
Absolute Event Rate: 55.1% vs 34.1%
p-value: p=<0.05
Combined modulation of BMP, FGF, and RA signaling pathways efficiently directs human induced pluripotent stem cells into sinoatrial node-like cells, providing a potential strategy for biological pacemaker construction.
Background: Biological pacemakers derived from pluripotent stem cell (PSC) have been considered as a potential therapeutic surrogate for sick sinus syndrome. So it’s essential to develop high efficient strategies for enrichment of sinoatrial node-like cells (SANLC) as seed cells for biological pacemakers. It has been reported that BMP, FGF and RA signaling pathways are involved in specification of different cardiomyocyte subtypes, pacemaker, ventricular, and atrial cells. Methods: During the differentiation process from human-induced pluripotent stem cell (hiPSC) to cardiomyocyte through small molecule based temporal modulation of the Wnt signaling pathway, signaling of BMP, FGF and RA was manipulated at cardiac mesoderm stage. qRT-PCR, immunofluorescence, flow cytometry and whole cell patch clamp were used to identify the SANLC. Results: qRT-PCR results showed that manipulating each one of bone morphogenetic protein (BMP), fibroblast growth factor (FGF) and retinoid acid (RA) signaling was effective for the upregulation of SANLC markers. Moreover, combined modulation of these three pathways displayed the best efficiency for the expression of SANLC markers, which was further confirmed at protein level using immunofluorescence and flow cytometry. Finally, the electrophysiological characteristics of upregulated SANLC were verified by patch clamp method. Conclusion: An efficient transgene-independent differentiation protocol for generating SANLC from hiPSC was developed, in which combined modulating BMP, FGF and RA signaling at cardiac mesoderm stage generates SANLC at high efficiency. This may serve as a potential approach for biological pacemaker construction.
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Liu et al. (2020) studied Sick sinus syndrome (in vitro model). Combined modulation of BMP, FGF, and RA signaling pathways (BMP4 + PD + BMS) vs. GiWi protocol (GSK3 inhibitor and Wnt inhibitor) was evaluated on Percentage of sinoatrial node-like cells (SANLC) defined by cTNT+/NKX2.5- (p=<0.05). Combined modulation of BMP, FGF, and RA signaling pathways during the cardiac mesoderm stage of hiPSC differentiation significantly increased the yield of sinoatrial node-like cells to 55.1% compared to 34.1% with the standard protocol.
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