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Repopulation of decellularized mouse heart with human induced pluripotent stem cell-derived cardiovascular progenitor cells

Nature Communications volume 4, Article number: 2307 (2013) | Download Citation

Abstract

Heart disease is the leading cause of death in the world. Heart tissue engineering holds a great promise for future heart disease therapy by building personalized heart tissues. Here we create heart constructs by repopulating decellularized mouse hearts with human induced pluripotent stem cell-derived multipotential cardiovascular progenitor cells. We show that the seeded multipotential cardiovascular progenitor cells migrate, proliferate and differentiate in situ into cardiomyocytes, smooth muscle cells and endothelial cells to reconstruct the decellularized hearts. After 20 days of perfusion, the engineered heart tissues exhibit spontaneous contractions, generate mechanical force and are responsive to drugs. In addition, we observe that heart extracellular matrix promoted cardiomyocyte proliferation, differentiation and myofilament formation from the repopulated human multipotential cardiovascular progenitor cells. Our novel strategy to engineer personalized heart constructs could benefit the study of early heart formation or may find application in preclinical testing.

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Acknowledgements

We thank Stephen Badylak and Jianyong Qi for technical support of mouse heart decellularization; Saik-Kia Goh and Ipsita Banerjee for technical support of DNA quantification; Stem Cell Core, University of Pittsburgh for support of stem cell culture; Cecilia Lo for kindly providing the MVP Total RNA of human fetal hearts; Cecilia Lo and Michael Tsang for critical reading of the manuscript. This work was supported by the University of Pittsburgh start-up and AHA SDG Grant #11SDG5580002 (to L.Y.) and by the National Science Council (Taiwan) Grant # NSC100-2917-I-564-015 (to T.-Y.L.).

Author information

Author notes

    • Tung-Ying Lu
    •  & Bo Lin

    These authors contributed equally to this work

Affiliations

  1. Department of Developmental Biology, University of Pittsburgh School of Medicine, Rangos Research Center, 530 45th Street, Pittsburgh, Pennsylvania 15201, USA

    • Tung-Ying Lu
    • , Bo Lin
    • , Kimimasa Tobita
    •  & Lei Yang
  2. Heart and Vascular Institute, University of Pittsburgh, School of Medicine, 3550 Terrace Street, S628 Scaife Hall, Pittsburgh, Pennsylvania 15261, USA

    • Jong Kim
    •  & Guy Salama
  3. CBI, University of Pittsburgh, 3500 Terrace Street, S233 BST, Pittsburgh, Pennsylvania 15261, USA

    • Mara Sullivan

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Contributions

L.Y. designed and oversaw all the studies. T.-Y.L. performed decellularization, ECM characterization, recellularization and assessments. B.L. performed cell culture, cardiovascular differentiation, PCR and IHC. M.S. conducted the electron microscopy. T.-Y.L., B.L. and L.Y. collected and analysed the data. J.K. and G.S. performed the optical mapping. G.S. and K.T. revised the manuscript. K.T. performed the mechanical testing. T.-Y.L., B.L. and L.Y. prepared the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Lei Yang.

Supplementary information

PDF files

  1. 1.

    Supplementary Figures and Table

    Supplementary Figures S1-S8 and Supplementary Table S1

Videos

  1. 1.

    Supplementary Movie 1

    Human Y1 iPS cell-derived beating EBs.

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    Supplementary Movie 2

    Day 20 contractile beating monolayers generated from the dissociated day 6 Y1 EBs cultured with VEGF (10 ng/ml) and DKK1 (150 ng/ml).

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    Supplementary Movie 3

    A contractile heart construct engineered with human RUES2 ES cells.

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    Supplementary Movie 4

    A contractile heart construct engineered with human Y1 iPS cells.

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    Supplementary Movie 5

    An electrically synchronized area in the iPS cell recellularized heart construct.

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    Supplementary Movie 6

    An electrically uncoupled area in the iPS cell recellularized heart construct. The uncoupled area can be synchronized with the electrical stimulation, which was loaded from the 5th to 10th second of the video.

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    Supplementary Movie 7

    Mechanical force recording of a RC-DC-ECM in response to 5 mM [Ca2+]out.

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    Supplementary Movie 8

    The engineered heart construct increased the active contractile force in response to 1.5 Hz electrical pacing. The electrical stimulation was loaded from the 10th to 20th second of the video.

About this article

Publication history

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DOI

https://doi.org/10.1038/ncomms3307

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