Myocardial Tissue Engineering with Cells Derived from Human-Induced Pluripotent Stem Cells and a Native-Like, High-Resolution, 3-Dimensionally Printed Scaffold

Ling Gao, Molly E. Kupfer, Jangwook P. Jung, Libang Yang, Patrick Zhang, Yong Da Sie, Quyen Tran, Visar Ajeti, Brian T. Freeman, Vladimir G. Fast, Paul J. Campagnola, Brenda M. Ogle, Jianyi Zhang

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Abstract

Rationale: Conventional 3-dimensional (3D) printing techniques cannot produce structures of the size at which individual cells interact. Objective: Here, we used multiphoton-excited 3D printing to generate a native-like extracellular matrix scaffold with submicron resolution and then seeded the scaffold with cardiomyocytes, smooth muscle cells, and endothelial cells that had been differentiated from human-induced pluripotent stem cells to generate a human-induced pluripotent stem cell-derived cardiac muscle patch (hCMP), which was subsequently evaluated in a murine model of myocardial infarction. Methods and Results: The scaffold was seeded with ≈50 000 human-induced pluripotent stem cell-derived cardiomyocytes, smooth muscle cells, and endothelial cells (in a 2:1:1 ratio) to generate the hCMP, which began generating calcium transients and beating synchronously within 1 day of seeding; the speeds of contraction and relaxation and the peak amplitudes of the calcium transients increased significantly over the next 7 days. When tested in mice with surgically induced myocardial infarction, measurements of cardiac function, infarct size, apoptosis, both vascular and arteriole density, and cell proliferation at week 4 after treatment were significantly better in animals treated with the hCMPs than in animals treated with cell-free scaffolds, and the rate of cell engraftment in hCMP-treated animals was 24.5% at week 1 and 11.2% at week 4. Conclusions: Thus, the novel multiphoton-excited 3D printing technique produces extracellular matrix-based scaffolds with exceptional resolution and fidelity, and hCMPs fabricated with these scaffolds may significantly improve recovery from ischemic myocardial injury.

Original languageEnglish (US)
Pages (from-to)1318-1325
Number of pages8
JournalCirculation research
Volume120
Issue number8
DOIs
StatePublished - Apr 14 2017

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Keywords

  • apoptosis
  • cardiomyocyte
  • endothelial cells
  • heart
  • myocardial infarction
  • tissue engineering

Cite this

Gao, L., Kupfer, M. E., Jung, J. P., Yang, L., Zhang, P., Da Sie, Y., Tran, Q., Ajeti, V., Freeman, B. T., Fast, V. G., Campagnola, P. J., Ogle, B. M., & Zhang, J. (2017). Myocardial Tissue Engineering with Cells Derived from Human-Induced Pluripotent Stem Cells and a Native-Like, High-Resolution, 3-Dimensionally Printed Scaffold. Circulation research, 120(8), 1318-1325. https://doi.org/10.1161/CIRCRESAHA.116.310277