Adipose tissue-derived stem cells as a therapeutic tool for cardiovascular disease

Abstract

Adipose tissue-derived stem cells (ADSCs) are adult stem cells that can be easily harvested from subcutaneous adipose tissue. Many studies have demonstrated that ADSCs differentiate into vascular endothelial cells (VECs), vascular smooth muscle cells (VSMCs), and cardiomyocytes in vitro and in vivo. However, ADSCs may fuse with tissue-resident cells and obtain the corresponding characteristics of those cells. If fusion occurs, ADSCs may express markers of VECs, VSMCs, and cardiomyocytes without direct differentiation into these cell types. ADSCs also produce a variety of paracrine factors such as vascular endothelial growth factor, hepatocyte growth factor, and insulin-like growth factor-1 that have proangiogenic and/or antiapoptotic activities. Thus, ADSCs have the potential to regenerate the cardiovascular system via direct differentiation into VECs, VSMCs, and cardiomyocytes, fusion with tissue-resident cells, and the production of paracrine factors. Numerous animal studies have demonstrated the efficacy of ADSC implantation in the treatment of acute myocardial infarction (AMI), ischemic cardiomyopathy (ICM), dilated cardiomyopathy, hindlimb ischemia, and stroke. Clinical studies regarding the use of autologous ADSCs for treating patients with AMI and ICM have recently been initiated. ADSC implantation has been reported as safe and effective so far. Therefore, ADSCs appear to be useful for the treatment of cardiovascular disease. However, the tumorigenic potential of ADSCs requires careful evaluation before their safe clinical application.

Keywords: Acute myocardial infarction; Adipose tissue-derived stem cells; Cardiovascular disease; Hindlimb ischemia; Ischemic cardiomyopathy; Stroke.

Figure 1

Schematic representation of LacZ expression following the excision of a floxed stop codon by Cre recombinase.

Figure 2

Possible mechanisms underlying the effect of adipose tissue-derived stem cells on regeneration of the cardiovascular system. ADSCs: Adipose tissue-derived stem cells; VEGF: Vascular endothelial growth factor; HGF: Hepatocyte growth factor; IGF-1: Insulin-like growth factor-1; bFGF: Basic fibroblast growth factor.

Figure 3

Ang-1 is implicated in Adipose tissue-derived stem cell-induced suppression of neointimal formation. A: ADSCs produce Ang-1, particularly when cultured in medium containing growth factors for VECs. Rat ADSCs were plated in 24-well plates and cultured in control medium (open circles) or medium containing growth factors for VECs (EGM: closed circles) for 1 wk. After washing with PBS, the medium was replaced with serum-free Dulbecco’s modified Eagle medium and incubated for the indicated periods. Ang-1 accumulation was measured with an enzyme-linked immunosorbent assay kit. ^aP < 0.05, ^bP < 0.01 vs 0 h (n = 6 per group); B: Effect of knockdown of endogenous Ang-1 in ADSCs and forced expression of Ang-1 on neointimal formation. ADSCs were infected with lentivirus expressing negative control siRNA (NCsiRNA), which does not suppress the expression of mammalian mRNA, or lentivirus expressing Ang-1 siRNA (Ang-1siRNA). ADSCs not infected with lentivirus were used as positive controls (ADSC). ADSCs were cultured in EGM for 1 wk. ADSCs (10⁶ cells) were seeded from the adventitial side immediately after wire injury of the rat femoral artery. Adenoviruses expressing green fluorescent protein (AdGFP) or Ang-1 (AdAng-1) were also injected into the femoral artery from the adventitial side following wire injury. Femoral arteries were harvested 14 d after injury for histological analyses. Arrowheads indicate the position of internal elastic lamina. Bars represent 100 μm; C: I/M ratios were compared among the groups (n = 8 per group). ^aP < 0.05 vs NCsiRNA infection and ^bP < 0.01 vs AdGFP infection. PBS: Phosphate-buffered saline; ADSCs: Adipose tissue-derived stem cells; VECs: Vascular endothelial cells.