METHOD FOR PRODUCING SINOATRIAL NODE CELLS (PACEMAKER CELLS) FROM STEM CELLS, AND USE OF THE PRODUCED SINOATRIAL NODE CELLS

摘要

The electric pacemakers currently used in the therapeutic approach for treating sick sinus syndrome cannot be hormonally regulated and pose the risk of infections or a premature battery discharge. These problems can be overcome by means of biological pacemakers obtained from pluripotent stem cells (PSC). It could be demonstrated that by differentiating stem cells in a controlled manner using TBX, sinoatrial node cell inductors, and an additional Myh6 promoter-specific antibiotic selection, cardiomyocyte aggregates are obtained, up to over 80% of which consists of physiologically functional pacemaker cells. For the first time, the induced sinoatrial nucleoli (iSABs) exhibited very high beat frequencies (300 - 400 bpm) similar to those in mouse hearts and were capable of rhythmically stimulating cardiac muscle cells ex vivo in a stable manner. Most of the genes in the iSAB transcriptome mapped using RNA-seq could be assigned to the ontologies of cardiac function/cardiac development and to the structures of contractile cells. Overall, this is the first example of highly pure and functional sinoatrial tissue derived from stem cells, thereby marking an important step towards a future cell therapy and in vitro testing of medications.