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

Research output: Contribution to journalArticle

80 Citations (Scopus)

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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Induced Pluripotent Stem Cells
Tissue Engineering
Cardiac Myocytes
Smooth Muscle Myocytes
Extracellular Matrix
Endothelial Cells
Myocardial Infarction
Calcium
Arterioles
Blood Vessels
Myocardium
Cell Proliferation
Apoptosis
Wounds and Injuries
Three Dimensional Printing

Keywords

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

Cite this

Myocardial Tissue Engineering with Cells Derived from Human-Induced Pluripotent Stem Cells and a Native-Like, High-Resolution, 3-Dimensionally Printed Scaffold. / Gao, Ling; Kupfer, Molly E.; Jung, Jangwook P.; Yang, Libang; Zhang, Patrick; Da Sie, Yong; Tran, Quyen; Ajeti, Visar; Freeman, Brian T.; Fast, Vladimir G.; Campagnola, Paul J.; Ogle, Brenda M.; Zhang, Jianyi.

In: Circulation research, Vol. 120, No. 8, 14.04.2017, p. 1318-1325.

Research output: Contribution to journalArticle

Gao, L, Kupfer, ME, Jung, JP, Yang, L, Zhang, P, Da Sie, Y, Tran, Q, Ajeti, V, Freeman, BT, Fast, VG, Campagnola, PJ, Ogle, BM & 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, vol. 120, no. 8, pp. 1318-1325. https://doi.org/10.1161/CIRCRESAHA.116.310277
Gao, Ling ; Kupfer, Molly E. ; Jung, Jangwook P. ; Yang, Libang ; Zhang, Patrick ; Da Sie, Yong ; Tran, Quyen ; Ajeti, Visar ; Freeman, Brian T. ; Fast, Vladimir G. ; Campagnola, Paul J. ; Ogle, Brenda M. ; Zhang, Jianyi. / Myocardial Tissue Engineering with Cells Derived from Human-Induced Pluripotent Stem Cells and a Native-Like, High-Resolution, 3-Dimensionally Printed Scaffold. In: Circulation research. 2017 ; Vol. 120, No. 8. pp. 1318-1325.
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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.",
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AU - Kupfer, Molly E.

AU - Jung, Jangwook P.

AU - Yang, Libang

AU - Zhang, Patrick

AU - Da Sie, Yong

AU - Tran, Quyen

AU - Ajeti, Visar

AU - Freeman, Brian T.

AU - Fast, Vladimir G.

AU - Campagnola, Paul J.

AU - Ogle, Brenda M.

AU - Zhang, Jianyi

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N2 - 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.

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KW - apoptosis

KW - cardiomyocyte

KW - endothelial cells

KW - heart

KW - myocardial infarction

KW - tissue engineering

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