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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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.).
Human Y1 iPS cell-derived beating EBs.
Day 20 contractile beating monolayers generated from the dissociated day 6 Y1 EBs cultured with VEGF (10 ng/ml) and DKK1 (150 ng/ml).
A contractile heart construct engineered with human RUES2 ES cells.
A contractile heart construct engineered with human Y1 iPS cells.
An electrically synchronized area in the iPS cell recellularized heart construct.
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.
Mechanical force recording of a RC-DC-ECM in response to 5 mM [Ca2+]out.
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
Nature Protocols (2014)