Transplantation of adipose stromal cells, but not mature adipocytes, augments ischemia-induced angiogenesis

Abstract

Therapeutic angiogenesis has emerged as a promising therapy to treat patients with ischemic diseases. Transplantation of bone marrow cells (BMCs) is reported to augment collateral development in ischemic organs either by differentiating into vascular cells or by secreting angiogenic cytokines. Recent evidence suggests that adipose tissues secrete a number of humoral factors and contain pluripotent stem cells. Here, we evaluated the therapeutic potential of adipose tissue-derived cells to promote angiogenesis in a mouse model of hind limb ischemia. Stromal vascular fraction cells (SVFs) were isolated from inguinal adipose tissue. Endothelial-like cells or smooth muscle-like cells could be obtained from the culture of SVFs in the presence of growth factors. Freshly isolated BMCs, SVFs, or mature adipocytes were transplanted into the ischemic hind limb of mice. SVFs significantly augmented collateral development as determined by the restoration of blood perfusion and capillary density of the ischemic muscle. Angiogenic effects of SVFs were as potent as those of BMCs. Mature adipocytes showed no proangiogenic effects. The ischemic muscle contained endothelial cells or smooth muscle cells that derived from the transplanted SVFs and BMCs. These results suggest that SVFs might be used to promote angiogenesis in ischemic tissues.

Introduction

Angiogenesis is a physiological response to ischemia (Folkman, 1995). In animal models of ischemia, a large body of evidence indicates that administration of angiogenic growth factors can augment nutrients perfusion through neovascularization (Freedman and Isner, 2001). Therapeutic angiogenesis, a strategy to cure tissue ischemia by promoting collateral growth, has emerged as one of the most promising therapies to date for ischemic diseases (Freedman and Isner, 2001). Although early clinical trials reported that the administration of angiogenic growth factors as a recombinant protein or gene could enhance the formation of new collateral vessels, relieving some ischemic symptoms (Freedman and Isner, 2001), the clinical efficacy of administration of a single growth factor is still controversial (Henry et al., 2003, Kastrup et al., 2005).

Accumulating evidence suggests that adult body may contain multipotent stem cells and/or progenitors of vascular endothelial cells and smooth muscle cells (Asahara et al., 1997, Sata, 2006, Simper et al., 2002). Animal and clinical studies demonstrated that transplanted bone marrow cells or endothelial progenitor cells promoted collateral formation in ischemic tissues by differentiating into vascular cells and/or by secreting angiogenic cytokines (Kamihata et al., 2001, Tateishi-Yuyama et al., 2002, Urbich and Dimmeler, 2004). Double blinded clinical studies are being performed to test the efficacy and the safety of autologous transplantation of bone marrow cells or ex vivo expanded autologous endothelial cells in patients with acute myocardial infarction (Drexler et al., 2006, Wollert et al., 2004). However, bone marrow aspiration is an invasive procedure that can not be performed frequently. Although endothelial progenitor cells could be mobilized into the systemic circulation by cytokines (Takahashi et al., 1999), the safety of the procedure is still controversial (Kang et al., 2004). Therefore, alternative source of stem cells or progenitors for therapeutic angiogenesis has been desired.

Recently, adipose tissues are reported to contain multipotent mesenchymal stem cells that have the ability to regenerate damaged organs (Gimble and Guilak, 2003, Miranville et al., 2004, Miyahara et al., 2006, Planat-Benard et al., 2004, Zuk et al., 2002). Here, we investigated therapeutic efficacy of stromal vascular fraction cells (SVFs) or mature adipocytes freshly isolated from adipose tissues in a murine model of hind limb ischemia. Results suggest that adipose-derived SVFs, but not mature adipocytes, are as potent as bone marrow cells in promoting angiogenesis when transplanted into ischemic tissues.