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Biomaterial-induced conversion of quiescent cardiomyocytes into pacemaker cells in rats

Nature Biomedical Engineering volume 6, pages 421–434 (2022)Cite this article

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Abstract

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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Fig. 1: SF-treated cardiomyocytes recapitulate membrane clock characteristics of genuine SANs.
Fig. 2: SF-treated cardiomyocytes recapitulate calcium clock characteristics of genuine SANs.
Fig. 3: Distinct structural features of SF-treated cardiomyocytes.
Fig. 4: The adhesion molecule Cdh5 underlies the mechanisms of pacemaker cell conversion.
Fig. 5: The upstream and downstream regulation of Cdh5.
Fig. 6: An in-situ surrogate SAN with biological pacemaker activities in rat ventricles.
Fig. 7: Persistence of the pacemaker phenotype.

Data availability

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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Acknowledgements

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.

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Authors and Affiliations

  1. Heart Rhythm Center, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

    Yu-Feng Hu, Shih-Lin Chang, Ching-Hui Weng, Pei-Chun Chou, Yung-Nan Tsai, Jin-Dian Liu & Shih-Ann Chen

  2. Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Yu-Feng Hu, Shih-Lin Chang & Shih-Ann Chen

  3. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

    Yu-Feng Hu, Chien-Chang Chen, Ruey-Bing Yang & Yuh-Charn Lin

  4. Department of Medicine, Mackay Medical College, New Taipei City, Taiwan

    An-Sheng Lee

  5. Institute of Biomedical Engineering, College of Electrical and Computer Engineering, National Yang Ming Chiao Tung University, Hsinchu, Taiwan

    Shien-Fong Lin & Yen-Ling Sung

  6. Department of Biomedical Engineering, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Hsin-Yu Lo & Tze-Wen Chung

  7. Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Terry B. J. Kuo & Cheng-Han Wu

  8. Center for Advanced Pharmaceutical Research and Drug Delivery, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Tze-Wen Chung

  9. Cardiovascular Center, Taichung Veterans General Hospital, Taichung, Taiwan

    Shih-Ann Chen

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Contributions

C.-H. Weng, P.-C.C. and J.-D.L. performed Ca2+ experiments, immunostaining, PCR and in vivo experiments. A.-S.L. and C.-C.C. performed the electrophysiological study in in vitro cardiomyocytes. Y.-N.T., S.-L.C., Y.-L.S. and S.-F.L. performed the Langendorff-perfused whole-heart study. R.-B.Y. and Y.-C.L. performed the experiments of Cdh5 promoter assay and shRNAs. T.B.J.K. and C.-H. Wu performed telemetry monitoring of rats. Y.-F.H. and T.-W.C. designed the project, performed the statistical analyses and wrote the manuscript. Y.F.H. performed the in vivo electrophysiological study of rats. H.-Y.L. and T.-W.C. prepared the biomaterial and performed its characterization. S.-A.C. contributed to revising the manuscript.

Corresponding authors

Correspondence to Yu-Feng Hu or Tze-Wen Chung.

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Supplementary information

Supplementary Information

Supplementary figures and tables, and captions for the supplementary videos and supplementary datasets.

Reporting Summary

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

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