Abstract
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.
Highlights
Heart failure after myocardial infarction (MI) remains a major clinical challenge despite recent advances in medicinal practice and cardiac transplantation, which are currently the two main treatment options [1,2]
We evaluated first whether spermine enhances the commitment of human adipose tissuederived multi-lineage progenitor cells (hADMPCs) into cardiomyocytes in vitro, which was tested by analyzing the mRNA expression of several cardiac differentiation markers by RT-PCR before and after treatment with spermine, including islet-1; Nkx2.5 and GATA-4; and α-cardiac actin (CA), myosin light chain (MLC), cardiac troponin I, and myosin heavy chain (MHC) (Figure 2A)
At day 1 post-induction, the expression levels of islet-1, Nkx2.5, GATA4, a-CA, MLC, cardiac troponin I, and MHC in hADMPC were 10.1, 660, 21, 95, 11, 13, 5.1 times higher than the baseline, respectively. These results indicated that the appropriate treatment-duration with spermine steered hADMPCs for commitment into cardiac lineage in vitro was 1 day
Summary
Heart failure after myocardial infarction (MI) remains a major clinical challenge despite recent advances in medicinal practice and cardiac transplantation, which are currently the two main treatment options [1,2]. Treatment using mesenchymal stem cells (MSCs) seems promising because these cells have immunoregulatory function, [6] and expand massively ex vivo without serious technical issues. In a series of publications, our group reported that adipose tissue-derived multi-lineage progenitor cells (ADMPC), which met the criteria of mesenchymal stem cells [9], could be reprogrammed into hepatocytes both in vitro and in vivo [10,11]. Human ADMPCs (hADMPCs) per se could not survive in cardiac parenchyme longer duration after transplantation and not differentiate into cardiomyocytes in vivo [12]. 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
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