Pacemaker cells can be differentiated from stem cells or transdifferentiated from quiescent mature cardiac cells via genetic manipulation. Here we show that the exposure of rat quiescent ventricular cardiomyocytes to a silk-fibroin hydrogel activates the direct conversion of the quiescent cardiomyocytes to pacemaker cardiomyocytes by inducing the ectopic expression of the vascular endothelial cell-adhesion glycoprotein cadherin. The silk-fibroin-induced pacemaker cells exhibited functional and morphological features of genuine sinoatrial-node cardiomyocytes in vitro, and pacemaker cells generated via the injection of silk fibroin in the left ventricles of rats functioned as a surrogate in situ sinoatrial node. Biomaterials with suitable surface structure, mechanics and biochemistry could facilitate the scalable production of biological pacemakers for human use.
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The main data supporting the results in this study are available within the paper and its Supplementary Information. The analysed datasets generated during the study are too large to be all publicly shared. A subset of the data, including source data and the data used to make the figures, are available from figshare with the identifier https://doi.org/10.6084/m9.figshare.14198261. More data are also available for research purposes from the corresponding authors on reasonable request. The dataset of the whole-transcriptome analysis (Fig. 4a) is available from the Sequence Read Archive (SRA) via the accession code PRJNA691697.
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We thank E. Marbán for reviewing the manuscript, W.-C. Wang for bioinformatics analysis, W.-H. Hsu for technical assistance, S.-C. Chou for flow cytometry analysis and the MiaoLi District Agriculture Research and Extension Station (Council of Agriculture, MiaoLi, Taiwan) for providing cocoons, which are also available for experimental reproduction by others. This work was supported by the Taipei Veterans General Hospital (V107C-029, VGHUST-107-G5-1-2, VGH108C-019, VN108-12, V110C-039), the Ministry of Science and Technology (105-2633-B-075-002, 107-2628-B-075-003, 108-2628-B-075-003, 107-2221-E-010-005-MY3, 110-2628-B-075-015), the National Health Research Institutes (NHRI-EX108-10513SC) and Academia Sinica (AS-TM-109-01-05, AS-TM-110-01-01). We also thank the National RNAi Core Facility at Academia Sinica in Taiwan for providing services, and C.-M. J. Hu for providing PEG-DA.
The authors declare no competing interests.
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Supplementary figures and tables, and captions for the supplementary videos and supplementary datasets.
Supplementary Video 1
Spontaneous whole-cell Ca2+ oscillations from control ventricular cardiomyocytes.
Supplementary Video 2
Spontaneous whole-cell Ca2+ oscillations from silk-fibroin ventricular cardiomyocytes.
Supplementary Video 3
Impulse propagation in a control rat heart by optical mapping.
Supplementary Video 4
Impulse propagation in a silk-fibroin-injected rat heart by optical mapping.
Supplementary Data 1
Differential gene expressions in Fig. 4a.
Supplementary Data 2
Canonical pathway analysis.
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Hu, YF., Lee, AS., Chang, SL. et al. Biomaterial-induced conversion of quiescent cardiomyocytes into pacemaker cells in rats. Nat. Biomed. Eng 6, 421–434 (2022). https://doi.org/10.1038/s41551-021-00812-y