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: 2.99). 03/2009; 123(2):475-85. DOI: 10.1097/PRS.0b013e3181954d08
Source: PubMed


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.

Full-text preview

Available from:
  • Source
    • "This methodology obviates the need for ex vivo cell expansion while avoiding the immunogenic concerns associated with allogeneic cell transplantation. The value of autologous cell therapies in patients with diabetes may be limited, however, as stem cell phenotypes can be negatively impacted by diabetes [14,15], and diabetic ASCs display an impaired neovascular potential in vitro[16]. Nonetheless, the therapeutic efficacy of diabetic ASCs within cutaneous wounds remains unclear [17]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction Pathophysiologic changes associated with diabetes impair new blood vessel formation and wound healing. Mesenchymal stem cells derived from adipose tissue (ASCs) have been used clinically to promote healing, although it remains unclear whether diabetes impairs their functional and therapeutic capacity. Methods In this study, we examined the impact of diabetes on the murine ASC niche as well as on the potential of isolated cells to promote neovascularization in vitro and in vivo. A novel single-cell analytical approach was used to interrogate ASC heterogeneity and subpopulation dynamics in this pathologic setting. Results Our results demonstrate that diabetes alters the ASC niche in situ and that diabetic ASCs are compromised in their ability to establish a vascular network both in vitro and in vivo. Moreover, these diabetic cells were ineffective in promoting soft tissue neovascularization and wound healing. Single-cell transcriptional analysis identified a subpopulation of cells which was diminished in both type 1 and type 2 models of diabetes. These cells were characterized by the high expression of genes known to be important for new blood vessel growth. Conclusions Perturbations in specific cellular subpopulations, visible only on a single-cell level, represent a previously unreported mechanism for the dysfunction of diabetic ASCs. These data suggest that the utility of autologous ASCs for cell-based therapies in patients with diabetes may be limited and that interventions to improve cell function before application are warranted.
    Full-text · Article · Jun 2014 · Stem Cell Research & Therapy
  • Source
    • "However, the regenerative capacity of these cells decreases with age and in patients with co-morbidities such as diabetes mellitus which reduces efficacy of autologous cell administration. Moreover, limited cell viability after transplantation into ischemic tissues also restricts their angiogenic potential [10-12]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Modified cell-based angiogenic therapy has become a promising novel strategy for ischemic heart and limb diseases. Most studies focused on myoblast, endothelial cell progenitors or bone marrow mesenchymal stromal cells transplantation. Yet adipose-derived stromal cells (in contrast to bone marrow) are abundantly available and can be easily harvested during surgery or liposuction. Due to high paracrine activity and availability ADSCs appear to be a preferable cell type for cardiovascular therapy. Still neither genetic modification of human ADSC nor in vivo therapeutic potential of modified ADSC have been thoroughly studied. Presented work is sought to evaluate angiogenic efficacy of modified ADSCs transplantation to ischemic tissue. Materials and methods Human ADSCs were transduced using recombinant adeno-associated virus (rAAV) serotype 2 encoding human VEGF165. The influence of genetic modification on functional properties of ADSCs and their angiogenic potential in animal models were studied. Results We obtained AAV-modified ADSC with substantially increased secretion of VEGF (VEGF-ADSCs). Transduced ADSCs retained their adipogenic and osteogenic differentiation capacities and adhesion properties. The level of angiopoetin-1 mRNA was significantly increased in VEGF-ADSC compared to unmodified cells yet expression of FGF-2, HGF and urokinase did not change. Using matrigel implant model in mice it was shown that VEGF-ADSC substantially stimulated implant vascularization with paralleling increase of capillaries and arterioles. In murine hind limb ischemia test we found significant reperfusion and revascularization after intramuscular transplantation of VEGF-ADSC compared to controls with no evidence of angioma formation. Conclusions Transplantation of AAV-VEGF- gene modified hADSC resulted in stronger therapeutic effects in the ischemic skeletal muscle and may be a promising clinical treatment for therapeutic angiogenesis.
    Full-text · Article · Jun 2013 · Journal of Translational Medicine
  • 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.
    Full-text · Article · Apr 2011 · Diabetes research and clinical practice
Show more