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Cell Spray Transplantation of Adipose-derived Mesenchymal Stem Cell Recovers Ischemic Cardiomyopathy in a Porcine Model

Mori, Daisuke, MD1; Miyagawa, Shigeru, MD, PhD1; Yajima, Shin, MD1; Saito, Shunsuke, MD, PhD1; Fukushima, Satsuki, MD, PhD1; Ueno, Takayoshi, MD, PhD1; Toda, Koichi, MD, PhD1; Kawai, Kotoe2,3; Kurata, Hayato2,3; Nishida, Hiroyuki2,3; Isohashi, Kayako, MD, PhD4; Hatazawa, Jun, MD, PhD4; Sawa, Yoshiki, MD, PhD1,5

doi: 10.1097/TP.0000000000002385
Original Basic Science—General

Background Allogeneic adipose-derived mesenchymal stem cells (ADSC) are promising cell sources for cell therapy to treat ischemic cardiomyopathy (ICM). We hypothesized that ADSC transplantation via the new cell spray method may be a feasible, safe, and effective treatment for ICM.

Methods Human ADSCs were acquired from white adipose tissue. Porcine ICM models were established by constriction of the left anterior descending coronary artery. Adipose-derived mesenchymal stem cells were spread over the surface of the heart via cell spray in fibrinogen and thrombin solutions. The cardiac function was compared with that of the control group.

Results Adipose-derived mesenchymal stem cells were successfully transplanted forming a graft-like gel film covering the infarct myocardium. Premature ventricular contractions were rarely detected in the first 3 days after transplantation. Echocardiography and magnetic resonance imaging revealed improved cardiac performance of the ADSC group at 4 and 8 weeks after transplantation. Systolic and diastolic parameters were significantly greater in the ADSC group at 8 weeks after transplantation. Histological examination showed significantly attenuated left ventricular remodeling and a greater vascular density in the infarct border area in the ADSC group. Moreover, the coronary flow reserve was maintained, and expression levels of angiogenesis-related factors in the infarct border and remote areas were significantly increased.

Conclusions Spray method implantation of allogenic ADSCs can improve recovery of cardiac function in a porcine infarction model. This new allogenic cell delivery system may help to resolve current limitations of invasiveness and cost in stem cell therapy.

The authors investigate a new method for cell therapy to treat ischemic cardiomyopathy and demonstrate that the spray method implantation of mesenchymal stem cells improves recovery of cardiac function in a porcine infarction model.

1 Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Suita, Japan.

2 Institute of Advanced Stem Cell Therapy, Osaka University, Osaka, Japan.

3 ROHTO Pharmaceutical Co., Ltd.

4 Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, Suita, Japan.

5 Medical Center for Translational Research, Osaka University Hospital, Osaka, Japan.

Received 14 April 2018. Revision received 19 May 2018.

Accepted 12 June 2018.

This study was supported by Rohto Pharmaceutical Co., Ltd. Y.S. serves as an advisor for the sponsor. Y.S. and S.M. received a speaking fee from the sponsor. K.K., H.K., and H.N. receive a salary from the sponsor where they are employees. The sponsor had no control over the interpretation, writing, or publication of this work. The terms of this arrangement have been reviewed and approved by Osaka University in accordance with its policy on objectivity in research.

This work was supported by the Department of Advanced Stem Cell Therapy (Rohto Pharmaceutical Co. Ltd.).

D.M. participated in research design performance of research, analyzed data, and wrote the article. S.Y., K.K., H.K., and H.N. performed research and analyzed data. K.I. and J.H. participated in performing PET.(helped with some experiments) S.S., S.F., T.U., and K.T. reviewed all data and article. S.M. and Y.S. participated in research design, writing of the article and reviewed all data and article. All authors have met the following criteria: drafting the work or revising it critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Correspondence: Yoshiki Sawa, MD, PhD, Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. (

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