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Spermine Treated-Adipose Tissue-Derived Multi-Lineage Progenitor Cells Improve Left Ventricular Dysfunction in a Swine Model of Chronic Myocardial Infarction

Hanayuki Okura, Mitsuko Morita, Maiko q Fujita, Kyoko Naba, Nozomi Hasebe-Takada, Akihiro Ichinose and Akifumi Matsuyama

Background: The polyamine spermine enhances differentiation of mouse embryonic stem cells into cardiac lineage. The aim of this study was to determine the effects of spermine on the differentiation of human adipose tissuederived multi-lineage progenitor cells (hADMPCs) into cardiomyocytes both in vitro and in vivo and any subsequent functional effect in a swine model of chronic myocardial infarction.

Methods and results: Spermine increased the expression of cardiac markers nkx2.5, islet-1, α-cardiac actin and cardiac troponin I (to 11.2-, 27.5-, 43.6- and 19.1-fold, relative to baseline, respectively) in hADMPCs. Chronic myocardial infarction model with left ventricular dysfunction was induced by balloon occlusion of the diagonal coronary artery followed by reperfusion, with subsequent similar procedure conducted one week later in the left ascending coronary artery (#6). Four weeks later, the immunosuppressed animals (with CyA 5.0 mg/kg intramuscularly (i.m) body weight/day) were transplanted with spermine-treated hADMPC (1×105 , 3×105 , 1×106 or 3×106 cells/kg body weight) via the coronary artery (#6). Cardiac function was assessed by echocardiography at 0, 4, 8 and 12 weeks post-transplantation. Transplantation of these cells improved cardiac function and the most effective dose was 3x105 cells/kg (ejection fraction; 33.4%, 47.0%, 51.5% and 52.9% at 0, 4, 8 and 12 weeks post-transplantation, respectively). At 12-week post-transplantation, spermine-treated hADMPCs differentiated into human-specific troponin I- and α-cardiac actin-positive cells in vivo.

Conclusion: Spermine induced differentiation of hADMPCs into cardiomyocytes both in vitro and in vivo and cellular cardiomyoplasty improved cardiac function. Cellular cardiomyoplasty using hADMPC could be potentially effective cell-based therapy.