TBX3 induces biased differentiation of human induced pluripotent stem cells into cardiac pacemaker-like cells

Background: TBX3 plays a critical role in the formation of the sinoatrial node (SAN) during embryonic heart development. However, the contribution of TBX3 in driving the differentiation of human induced pluripotent stem cells (hiPSC)into pacemaker cells remains to be explored. Results: Using the pan-cardiomyocyte differentiation protocol of human induced pluripotent stem cells (hiPSC), TBX3 gene was introduced into the differentiating hiPSC on day 5 post-differentiation, and the differentiation of pacemaker-like cardiomyocytes was evaluated on day 21. The results showed that TBX3 significantly induced biased differentiation of hiPSC into pacemaker-like cells as judged by significantly increased expression of SANspecific marker gene, SHOX2, and slightly decreased expression of SAN-detrimental transcription factor, NKX2-5. Conclusion: Our results suggest that TBX3 plays an important role in driving the differentiation of hiPSC into pacemaker-like cells, and manipulation of TBX3 expression during pan-cardiomyocyte differentiation may lead to the development of therapeutic pacemaker cells.