Large Cardiac Muscle Patches Engineered From Human Induced-Pluripotent Stem Cell–Derived Cardiac Cells Improve Recovery From Myocardial Infarction in Swine

DOI Web Site 9 Citations
  • Ling Gao
    Department of Biomedical Engineering, School of Medicine and School of Engineering, University of Alabama at Birmingham (L.G., W.Z., S.M., Y.O., X.LO., R.K., A.V.B., G.P.W., A.E.P., V.G.F., S.G.L., J.Z.).
  • Zachery R. Gregorich
    Department of Cell and Regenerative Biology, University of Wisconsin-Madison (Z.R.G., Y.G.).
  • Wuqiang Zhu
    Department of Biomedical Engineering, School of Medicine and School of Engineering, University of Alabama at Birmingham (L.G., W.Z., S.M., Y.O., X.LO., R.K., A.V.B., G.P.W., A.E.P., V.G.F., S.G.L., J.Z.).
  • Saidulu Mattapally
    Department of Biomedical Engineering, School of Medicine and School of Engineering, University of Alabama at Birmingham (L.G., W.Z., S.M., Y.O., X.LO., R.K., A.V.B., G.P.W., A.E.P., V.G.F., S.G.L., J.Z.).
  • Yasin Oduk
    Department of Biomedical Engineering, School of Medicine and School of Engineering, University of Alabama at Birmingham (L.G., W.Z., S.M., Y.O., X.LO., R.K., A.V.B., G.P.W., A.E.P., V.G.F., S.G.L., J.Z.).
  • Xi Lou
    Department of Biomedical Engineering, School of Medicine and School of Engineering, University of Alabama at Birmingham (L.G., W.Z., S.M., Y.O., X.LO., R.K., A.V.B., G.P.W., A.E.P., V.G.F., S.G.L., J.Z.).
  • Ramaswamy Kannappan
    Department of Biomedical Engineering, School of Medicine and School of Engineering, University of Alabama at Birmingham (L.G., W.Z., S.M., Y.O., X.LO., R.K., A.V.B., G.P.W., A.E.P., V.G.F., S.G.L., J.Z.).
  • Anton V. Borovjagin
    Department of Biomedical Engineering, School of Medicine and School of Engineering, University of Alabama at Birmingham (L.G., W.Z., S.M., Y.O., X.LO., R.K., A.V.B., G.P.W., A.E.P., V.G.F., S.G.L., J.Z.).
  • Gregory P. Walcott
    Department of Biomedical Engineering, School of Medicine and School of Engineering, University of Alabama at Birmingham (L.G., W.Z., S.M., Y.O., X.LO., R.K., A.V.B., G.P.W., A.E.P., V.G.F., S.G.L., J.Z.).
  • Andrew E. Pollard
    Department of Biomedical Engineering, School of Medicine and School of Engineering, University of Alabama at Birmingham (L.G., W.Z., S.M., Y.O., X.LO., R.K., A.V.B., G.P.W., A.E.P., V.G.F., S.G.L., J.Z.).
  • Vladimir G. Fast
    Department of Biomedical Engineering, School of Medicine and School of Engineering, University of Alabama at Birmingham (L.G., W.Z., S.M., Y.O., X.LO., R.K., A.V.B., G.P.W., A.E.P., V.G.F., S.G.L., J.Z.).
  • Xinyang Hu
    Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China (X.H.).
  • Steven G. Lloyd
    Department of Biomedical Engineering, School of Medicine and School of Engineering, University of Alabama at Birmingham (L.G., W.Z., S.M., Y.O., X.LO., R.K., A.V.B., G.P.W., A.E.P., V.G.F., S.G.L., J.Z.).
  • Ying Ge
    Department of Cell and Regenerative Biology, University of Wisconsin-Madison (Z.R.G., Y.G.).
  • Jianyi Zhang
    Department of Biomedical Engineering, School of Medicine and School of Engineering, University of Alabama at Birmingham (L.G., W.Z., S.M., Y.O., X.LO., R.K., A.V.B., G.P.W., A.E.P., V.G.F., S.G.L., J.Z.).

Description

<jats:sec> <jats:title>Background:</jats:title> <jats:p>Here, we generated human cardiac muscle patches (hCMPs) of clinically relevant dimensions (4 cm × 2 cm × 1.25 mm) by suspending cardiomyocytes, smooth muscle cells, and endothelial cells that had been differentiated from human induced-pluripotent stem cells in a fibrin scaffold and then culturing the construct on a dynamic (rocking) platform.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>In vitro assessments of hCMPs suggest maturation in response to dynamic culture stimulation. In vivo assessments were conducted in a porcine model of myocardial infarction (MI). Animal groups included: MI hearts treated with 2 hCMPs (MI+hCMP, n=13), MI hearts treated with 2 cell-free open fibrin patches (n=14), or MI hearts with neither experimental patch (n=15); a fourth group of animals underwent sham surgery (Sham, n=8). Cardiac function and infarct size were evaluated by MRI, arrhythmia incidence by implanted loop recorders, and the engraftment rate by calculation of quantitative polymerase chain reaction measurements of expression of the human Y chromosome. Additional studies examined the myocardial protein expression profile changes and potential mechanisms of action that related to exosomes from the cell patch.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>The hCMPs began to beat synchronously within 1 day of fabrication, and after 7 days of dynamic culture stimulation, in vitro assessments indicated the mechanisms related to the improvements in electronic mechanical coupling, calcium-handling, and force generation, suggesting a maturation process during the dynamic culture. The engraftment rate was 10.9±1.8% at 4 weeks after the transplantation. The hCMP transplantation was associated with significant improvements in left ventricular function, infarct size, myocardial wall stress, myocardial hypertrophy, and reduced apoptosis in the periscar boarder zone myocardium. hCMP transplantation also reversed some MI-associated changes in sarcomeric regulatory protein phosphorylation. The exosomes released from the hCMP appeared to have cytoprotective properties that improved cardiomyocyte survival.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>We have fabricated a clinically relevant size of hCMP with trilineage cardiac cells derived from human induced-pluripotent stem cells. The hCMP matures in vitro during 7 days of dynamic culture. Transplantation of this type of hCMP results in significantly reduced infarct size and improvements in cardiac function that are associated with reduction in left ventricular wall stress. The hCMP treatment is not associated with significant changes in arrhythmogenicity.</jats:p> </jats:sec>

Journal

  • Circulation

    Circulation 137 (16), 1712-1730, 2018-04-17

    Ovid Technologies (Wolters Kluwer Health)

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