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Title: Human iPS cell-derived cardiac tissue sheets for functional restoration of infarcted porcine hearts
Authors: Ishigami, Masanosuke
Masumoto, Hidetoshi  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0002-4059-2827 (unconfirmed)
Ikuno, Takeshi
Aoki, Takayuki
Kawatou, Masahide
Minakata, Kenji
Ikeda, Tadashi  kyouindb  KAKEN_id
Sakata, Ryuzo
Yamashita, Jun K.
Minatoya, Kenji
Author's alias: 石上, 雅之助
升本, 英利
幾野, 毅
青木, 隆之
川東, 正英
南方, 謙二
池田, 義
坂田, 隆造
山下, 潤
湊谷, 謙司
Issue Date: 2-Aug-2018
Publisher: Public Library of Science (PLoS)
Journal title: PLOS ONE
Volume: 13
Issue: 8
Thesis number: e0201650
Abstract: To realize human induced pluripotent stem cell (hiPSC)-based cardiac regenerative therapy, evidence of therapeutic advantages in human-sized diseased hearts are indispensable. In combination with an efficient and simultaneous differentiation of various cardiac lineages from hiPSCs and cell sheet technology, we aimed to generate clinical-sized large cardiac tissue sheets (L-CTSs) and to evaluate the therapeutic potential in porcine infarct heart. We simultaneously induced cardiomyocytes (CMs) and vascular cells [vascular endothelial cells (ECs) and vascular mural cells (MCs)] from hiPSCs. We generated L-CTSs using 10cm-sized temperature-responsive culture dishes. We induced myocardial infarction (MI) in micromini-pigs (15–25 kg) and transplanted the L-CTSs (Tx) 2 weeks after MI induction (4 sheets/recipient) under immunosuppression (Tx: n = 5, Sham: n = 5). Self-pulsating L-CTSs were approximately 3.5cm in diameter with 6.8×10⁶±0.8 of cells containing cTnT⁺-CMs (45.6±13.2%), VE-cadherin⁺-ECs (5.3±4.4%) and PDGFRβ⁺-MCs (14.4±20.7%), respectively (n = 5). In Tx group, echocardiogram indicated a significantly higher systolic function of the left ventricle (LV) compared to that in sham control (Sham vs Tx: fractional shortening: 24.2±8.6 vs 40.5±9.7%; p<0.05). Ejection fraction evaluated by left ventriculogram was significantly higher in Tx group (25.3±6.2% vs 39.8±4.2%; p<0.01). Speckle tracking echocardiogram showed a significant increase of circumference strain in infarct and border regions after transplantation. Fibrotic area was significantly lower in Tx group (23.8±4.5 vs 15.9±3.8%; P<0.001). Capillary density in the border region was significantly higher in Tx group (75.9±42.6/mm² vs 137.4±44.8/mm², p<0.001). These data indicate that the L-CTS transplantation attenuated LV remodeling. L-CTSs potentially restore cardiac dysfunction of human-sized infarct heart.
Rights: © 2018 Ishigami et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
URI: http://hdl.handle.net/2433/236167
DOI(Published Version): 10.1371/journal.pone.0201650
PubMed ID: 30071102
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