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Regeneration of infarcted mouse hearts by cardiovascular tissue formed via the direct reprogramming of mouse fibroblasts

Abstract

Fibroblasts can be directly reprogrammed into cardiomyocytes, endothelial cells or smooth muscle cells. Here we report the reprogramming of mouse tail-tip fibroblasts simultaneously into cells resembling these three cell types using the microRNA mimic miR-208b-3p, ascorbic acid and bone morphogenetic protein 4, as well as the formation of tissue-like structures formed by the directly reprogrammed cells. Implantation of the formed cardiovascular tissue into the infarcted hearts of mice led to the migration of reprogrammed cells to the injured tissue, reducing regional cardiac strain and improving cardiac function. The migrated endothelial cells and smooth muscle cells contributed to vessel formation, and the migrated cardiomyocytes, which initially displayed immature characteristics, became mature over time and formed gap junctions with host cardiomyocytes. Direct reprogramming of somatic cells to make cardiac tissue may aid the development of applications in cell therapy, disease modelling and drug discovery for cardiovascular diseases.

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Fig. 1: Reprogramming of fibroblasts into cardiomyocyte-like cells and a tissue-like structure.
Fig. 2: Reprogramming toward endothelial cells.
Fig. 3: Reprogramming towards SMCs.
Fig. 4: Transcriptome analysis.
Fig. 5: Transplantation of rCVT on MI heart.
Fig. 6: Functional vessel formation by rCVT at week 4.
Fig. 7: Functional vessel formation by rCVT at week 16.
Fig. 8: Cardiomyogenesis induced by rCVT.

Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are too large to be publicly shared, but they are available for research purposes from the corresponding author on reasonable request. The RNA-seq data are available from the Gene Expression Omnibus under accession GSE96617, and the scRNA-seq data are available under accessions GSE179589, GSM5420997 and GSM5420998Source data are provided with this paper.

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Acknowledgements

We thank J. V. Taylor for sample preparations for TEM images and J. Mobley at the University of Alabama at Birmingham Comprehensive Cancer Center Mass Spectrometry/Proteomics Shared Facility for LC–MS analysis. This work was supported by grants from the National Heart, Lung, and Blood Institute (R01HL150877, R61HL154116, R01HL129511 and R01HL125391), an American Heart Association Transformative Project Award and the Bio and Medical Technology Development Program of the National Research Foundation grant funded by the Korean government (MSIT) (2020M3A9I4038454, 2020R1A2C3003784 and 2017R1D1A1B03036063).

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Authors

Contributions

J.C. and Y.-s.Y. conceived the project and designed experiments. J.C. performed most experiments. S.K., S.B. and H.-J.P. performed surgical experiments. H.L. and W.R. conducted RT–qPCR and flow cytometry analysis. H.C.C. and N.K.K. performed cardiac arrhythmia studies and contributed to manuscript writing. H.Y. conducted TEM. D.H.S. and M.G.L. performed action potential measurement. Y.T., I.-H.P., H.L., J.W.H. and S.B. contributed to total and scRNA-seq data analysis. P.T.J.H. and H.-W.J. contributed to LC–MS protein analysis. H.L. and K.C. contributed to isolation of adult cardiomyocytes. H.L., W.R., S.W.L. and J.K.J. contributed to mouse breeding and fibroblast culture. E.S. and R.D.L. measured cardiac strain. M.A.S. and R.P.H. provided transgenic mice and helpful suggestions. J.C., H.C.C., J.W.H. and Y.-s.Y. analysed data, and J.C. and Y.-s.Y. wrote the manuscript.

Corresponding author

Correspondence to Young-sup Yoon.

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The authors declare no competing interests.

Additional information

Peer review information Nature Biomedical Engineering thanks Igor Efimov, Masayuki Yazawa and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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Extended data

Extended Data Fig. 1 Increased mRNA expression of CM genes in reprogramming fibroblasts.

mRNA expression of CM genes after the indicated treatment. Expression in MTTFs was set as 1 and U indicates undetected. Ten independent experiments, each with technical replicates. ***P < 0.001: MAB vs MTTF, AA, BMP4, AA/BMP4 and miR-208b. Statistical analysis was performed using one-way ANOVA with Bonferroni’s multiple comparison test. Data are mean ± SEM.

Source data

Extended Data Fig. 2 Transcriptome changes during the reprogramming of fibroblasts in total RNA-seq analysis.

a, 3D PCA plot of fibroblasts (D0), reprogrammed cells (D6 & D10), fetal heart, ECs, SMCs and CMs. b, Relative enrichment of gene signatures for heart, ECs, SMCs and CMs in D6 and D10 reprogrammed cells. Genes are sorted by relative expression to D0 (fibroblasts). The presence of gene signatures is shown by black bars. Normalized enrichment score (NES); statistical significance (FDR). c, Heatmap showing expression of fibroblast markers.

Extended Data Fig. 3 No arrhythmogenic potential of rCVT in infarcted hearts.

a, Representative electrocardiograms of premature ventricular contractions (PVCs, arrows) in MI mice transplanted with d-rCVT (n = 5) or rCVT (n = 5). Telemetry was implanted at day 2 to lessen the surgical trauma to the acute MI animals at day 0. b-c, Representative electrocardiograms of MI mice transplanted with d-rCVT (b) or rCVT (c) upon programmed electrical stimulation after ECG monitoring for 30 days. VT: ventricular tachycardia.

Supplementary information

Supplementary Information

Supplementary figures and table and video captions.

Reporting Summary

Supplementary Table 1

A primer list for RT–qPCR.

Supplementary Table 2

Differentially expressed genes across heart, endothelial cell, SMC and CM.

Supplementary Table 3

Gene information of clusters 7, 8 and 9 identified in the scRNA-seq data of reprogrammed cells.

Supplementary Video 1

Spontaneous contractions of MTTFs treated with MAB.

Supplementary Video 2

Calcium transients of MTTFs treated with MAB.

Supplementary Video 3

3D view of a vessel with rEC and rSMC.

Peer Review Information

Source data

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Source Data for Fig. 2

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Source Data for Fig. 3

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Data for Fig. 5

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Source Data for Extended Data Fig. 1

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Cho, J., Kim, S., Lee, H. et al. Regeneration of infarcted mouse hearts by cardiovascular tissue formed via the direct reprogramming of mouse fibroblasts. Nat Biomed Eng 5, 880–896 (2021). https://doi.org/10.1038/s41551-021-00783-0

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