Sirtuin1 Regulates the Stem Cell Therapeutic Effects on Regenerative Capability for Treating Severe Heart Failure in a Juvenile Animal Model

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• 作者：Hideto Ozawa ; MD ; Shigeru Miyagawa ; MD ; PhD ; Satsuki Fukushima ; MD ; PhD ; Emiko Itoh ; PhD ; Akima Harada ; BD ; Atsuhiro Saito ; PhD ; Takayoshi Ueno ; MD ; PhD ; Koichi Toda ; MD ; PhD ; Toru Kuratani ; MD ; PhD ; Yoshiki Sawa ; MD ; PhD ; ^{sawa-p@surg1.med.osaka-u.ac.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：HF ; heart failure ; HGF ; hepatocyte growth factor ; HIF ; hypoxia-induced factor ; KD ; knockdown ; LVEF ; left ventricular ejection fraction ; MRI ; magnetic resonance imaging ; NF-κB ; nuclear factor-κB ; SDF-1 ; stromal cell&ndash ; derived factor-1 ; SIRT ; sirtuin ; SS ; skeletal stem ; VEGF ; vascular endothelial growth factor
• 刊名：The Annals of Thoracic Surgery
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：102
• 期：3
• 页码：803-812
• 全文大小：2492 K

文摘

This study hypothesized that autologous cell transplantation therapy could have greater therapeutic efficacy in juvenile patients than in adult patients, related to differences in sirtuin1 (SIRT1) expression in transplanted cells.

Methods

A model of heart failure was established in mini-pigs by using coronary artery occlusion. Stem cell cultures were established from juvenile and adult mini-pigs. The cells were prepared as cell sheets and transplanted into corresponding adult or juvenile mini-pigs, and the therapeutic effects were examined in vivo and in vitro. Next, SIRT1 knockdown cells were established using small interfering RNAs for SIRT1, and the therapeutic effects of the cells were examined in vitro and in vivo in Lewis rat models of heart failure.

Results

Cardiac function showed significantly more improvement in juvenile than in adult pigs. Histologic analysis revealed significant reduction of myocardial fibrosis and hypertrophic response in juvenile pigs. In vitro analysis demonstrated that doubling time was significantly shorter, the ratio of Ki67-positive cells was significantly greater, and the expression of SIRT1, hypoxia-induced factor-1α, hepatocyte growth factor, and stromal cell–derived factor-1 was significantly upregulated in juvenile cells. SIRT1 knockdown cells showed decreased proliferation and cytokine release potential compared with wild-type cells. Transplantation of SIRT1 knockdown stem cell sheets showed lesser improvement of cardiac function after severe heart failure in Lewis rats than in controls.

Conclusions

Sirtuin1 expression in transplanted cells enhances the skeletal stem cell sheet therapeutic effects for treating severe heart failure in a juvenile animal model.