Aging and Diabetes Impair the Neovascular Potential of Adipose-Derived Stromal Cells

Department of Surgery, Division of Plastic Surgery, Stanford University School of Medicine, Stanford, California, USA.
Plastic and Reconstructive Surgery (Impact Factor: 3.33). 03/2009; 123(2):475-85. DOI: 10.1097/PRS.0b013e3181954d08
Source: PubMed

ABSTRACT Aging and diabetes are major risk factors for poor wound healing and tissue regeneration that reflect an impaired ability to respond to ischemic insults. The authors explored the intrinsic neovascular potential of adipose-derived stromal cells in the setting of advanced age and in type 1 and type 2 diabetes.
Adipose-derived stromal cells isolated from young, aged, streptozotocin-induced, and db/db diabetic mice were exposed to normoxia and hypoxia in vitro. Vascular endothelial growth factor (VEGF) expression, proliferation, and tubulization were measured. Conditioned media harvested from adipose-derived stromal cell cultures were assessed for their ability to stimulate human umbilical vein endothelial cell proliferation (n = 3 and n = 3).
Young adipose-derived stromal cells demonstrated significantly higher levels of VEGF production, proliferation, and tubulogenesis than those derived from aged, streptozotocin-induced, and db/db mice in both normoxia and hypoxia. Although aged and diabetic adipose-derived stromal cells retained the ability to up-regulate VEGF secretion, proliferation, and tubulogenesis in response to hypoxia, the response was blunted compared with young controls. Conditioned media derived from these cells cultured in normoxia in vitro also had a significantly greater ability to increase human umbilical vein endothelial cell proliferation compared with media harvested from aged, streptozotocin-induced, and db/db adipose-derived stromal cells. This effect was magnified in conditioned media harvested from hypoxic adipose-derived stromal cell cultures.
This study demonstrates that aging and type 1 and type 2 diabetes impair intrinsic adipose-derived stromal cell function; however, these cells may still be a suitable source of angiogenic cells that can potentially improve neovascularization of ischemic tissues.

  • Source
    • "In diabetes, basic studies have shown that BMMSCs could not only relieve hind limb ischemia [19] but also accelerate wound healing [20]. Although the neovascular potential of both BMMNCs and BMMSCs from diabetic rats was impaired [21] [22], one clinical trial has shown that applied BMMNCs could restore angiogenesis and promote wound healing in diabetic patients [23]. However, few reports have shown the safety and efficacy of ex vivo expanded BMMSCs, or have compared BMMSCs with BMMNCs in the treatment of diabetic CLI and foot ulcers. "
    [Show abstract] [Hide abstract]
    ABSTRACT: To identify better cells for the treatment of diabetic critical limb ischemia (CLI) and foot ulcer in a pilot trial. Under ordinary treatment, the limbs of 41 type 2 diabetic patients with bilateral CLI and foot ulcer were injected intramuscularly with bone marrow mesenchymal stem cells (BMMSCs), bone marrow-derived mononuclear cells (BMMNCs), or normal saline (NS). The ulcer healing rate of the BMMSC group was significantly higher than that of BMMNCs at 6 weeks after injection (P=0.022), and reached 100% 4 weeks earlier than BMMNC group. After 24 weeks of follow-up, the improvements in limb perfusion induced by the BMMSCs transplantation were more significant than those by BMMNCs in terms of painless walking time (P=0.040), ankle-brachial index (ABI) (P=0.017), transcutaneous oxygen pressure (TcO(2)) (P=0.001), and magnetic resonance angiography (MRA) analysis (P=0.018). There was no significant difference between the groups in terms of pain relief and amputation and there was no serious adverse events related to both cell injections. BMMSCs therapy may be better tolerated and more effective than BMMNCs for increasing lower limb perfusion and promoting foot ulcer healing in diabetic patients with CLI.
    Diabetes research and clinical practice 04/2011; 92(1):26-36. DOI:10.1016/j.diabres.2010.12.010 · 2.54 Impact Factor
  • Source
    • "Neovascularization is a critical component of normal wound healing, and impairments in this process are highly implicated in diabetic and aged wound healing [32]. However, new Table 1: Major differences between mouse and human skin. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Wound repair is a complex biologic process which becomes abnormal in numerous disease states. Although in vitro models have been important in identifying critical repair pathways in specific cell populations, in vivo models are necessary to obtain a more comprehensive and pertinent understanding of human wound healing. The laboratory mouse has long been the most common animal research tool and numerous transgenic strains and models have been developed to help researchers study the molecular pathways involved in wound repair and regeneration. This paper aims to highlight common surgical mouse models of cutaneous disease and to provide investigators with a better understanding of the benefits and limitations of these models for translational applications.
    BioMed Research International 01/2011; 2011(1110-7243):969618. DOI:10.1155/2011/969618 · 2.71 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Overcoming the effects of hyperglycemic conditions on matrix remodeling by cardiac fibroblasts represents a novel therapeutic approach to stimulate regeneration of cardiac tissue in the context of diabetes. The purpose of this study was to investigate the effects of diabetic conditions on the extracellular matrix (ECM) protein expression and biomechanical response of cardiac fibroblasts. Two types of diabetic conditions were used: in vivo using rat model of diabetic cardiomyopathy (DCM), or in vitro using high glucose culture medium. A commercially available Flexcell system was used to apply uniaxial stretch to rat cardiac fibroblasts, and cell response was assessed, including MMP-2 (ECM remodeling), collagen I (ECM deposition), and vascular endothelial growth factor (cell migration stimulus) expression as well as fibroblast morphology, orientation, proliferation and apoptosis. The results demonstrate differential cell responses to the two models of diabetic condition. Cardiac fibroblasts from the in vivo rat model of DCM exhibited an overall reduced synthetic activity and proliferation, while high glucose conditions lead to apparent increases in cell responses. In the in vivo rat model, exposure to cyclic strain appeared to act toward restoration of cell proliferation and collagen I expression that were decreased with diabetes.
    Cellular and Molecular Bioengineering 06/2012; 5(2). DOI:10.1007/s12195-012-0222-2 · 1.23 Impact Factor
Show more


1 Download
Available from