Locally Delivered Growth Factor Enhances the Angiogenic Efficacy of Adipose-Derived Stromal Cells Transplanted to Ischemic Limbs

Abstract

Ischemia is a potentially fatal medical event that is associated with as many as 30 percent of all deaths. Stem cell therapy offers significant therapeutic promise, but poor survival following transplantation to ischemic tissue limits its efficacy. Here we demonstrate that nanosphere-mediated growth factor delivery can enhance the survival of transplanted human adipose-derived stromal cells (hADSCs) and secretion of human angiogenic growth factors per cell, and substantially improve therapeutic efficacy of hADSCs. In vitro, in hypoxic (1% oxygen) and serum-deprived conditions which simulate in vivo ischemia, fibroblast growth factor-2 (FGF2) significantly reduced hADSC apoptosis and enhanced angiogenic growth factor secretion. In vivo, hADSCs delivered intramuscularly into ischemic hindlimbs in combination with FGF2 resulted in significant improvements in limb survival and blood perfusion, as well as survival of the transplanted hADSCs and secretion of human angiogenic growth factors (i.e., vascular endothelial growth factor, hepatocyte growth factor, and FGF2). Interestingly, the majority of transplanted hADSCs were localized adjacent to the microvessels rather than being incorporated into them, suggesting that their major contribution to angiogenesis might be to increase paracrine secretion of angiogenic growth factors. This study demonstrates the potential of hADSCs in combination with growth factors for use in the treatment of ischemia.

Transplantation of freshly isolated adipose tissue-derived regenerative cells enhances angiogenesis in a murine model of hind limb ischemia

“…3). It is well known that these factors promote cell proliferation, migration, and mobilization (3,20,22). As a complement of these results, HUVECs stimulated by angiogenic factors from fADRCs formed tubelike structures more effectively than cADRCs-stimulated HUVECs (Fig.…”

Long-term Angiogenesis Efficacy Using a Heparin-Conjugated Fibrin (HCF) Delivery System with HBM-MSCs

“…Induction of angiogenesis via injection of various angiogenic growth factors (4,5) and stem cells (9,10) has been shown to improve ischemic conditions. However, growth factors are generally not sufficiently stable to exert significant biological activity due to a short half-life, whereas stem cells exhibit poor cell survival after transplantation Fig.…”

“…A previous study showed that local delivery of bFGF to ischemic tissue to which ADSCs had been previously transplanted improves the survival of transplanted ADSCs for a short duration (10), suggesting that bFGF binding of HCF may increase its stability and prolong its half-life. Further, HCF delivery systems enhance the angiogenic efficacy of bFGF compared with normal fibrin in a mouse limb ischemia model (24,27).…”

“…In addition, therapeutic angiogenesis can be achieved by injection of stem cells such as endothelial progenitor cells (7), bone marrow cells (BMCs) (8,9), and adipose-derived stromal cells (ADSCs) (10). However, therapies consisting of single injections of angiogenic growth factors or stem cells have a limited ability to promote angiogenesis due to poor survival rates of injected stem cells and limited duration of the biological activity of injected growth factors (11)(12)(13)(14).…”

“…However, therapies consisting of single injections of angiogenic growth factors or stem cells have a limited ability to promote angiogenesis due to poor survival rates of injected stem cells and limited duration of the biological activity of injected growth factors (11)(12)(13)(14). In response to this lack of efficacy of single agents, many studies have utilized combined injections of growth factors and stem cells; however, in such cases, the duration of the biological activity of growth factors in vivo is extremely short (10,15,16). Thus, additional methods to improve the biological activity of growth factors in vivo have been studied (17)(18)(19).…”