Novel Autologous Cell Therapy in Ischemic Limb Disease Through Growth Factor Secretion by Cultured Adipose Tissue–Derived Stromal Cells

Abstract

Objective-The delivery of autologous progenitor cells into ischemic tissue of patients is emerging as a novel therapeutic option. Here, we report the potential impact of cultured adipose tissue-derived cells (ADSC) on angiogenic cell therapy. Method and Results-ADSC were isolated from C57Bl/6 mouse inguinal adipose tissue and showed high expression of ScaI and CD44, but not c-kit, Lin, CD34, CD45, CD11b, and CD31, compatible with that of mesenchymal stem cells from bone marrow. In coculture conditions with ADSC and human aortic endothelial cells (ECs) under treatment with growth factors, ADSC significantly increased EC viability, migration and tube formation mainly through secretion of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF). At 4 weeks after transplantation of ADSC into the ischemic mouse hindlimb, the angiogenic scores were improved in the ADSC-treated group, which were evaluated with blood flow by laser Doppler imaging (LDI) and capillary density by immunostaining with anti-CD31 antibody. However, injected ADSC did not correspond to CD31, von Willebrand factor, and ␣-smooth muscle actin-positive cells in ischemic tissue. Conclusion-These

<b>Adipose stem cell sheets improved cardiac function in the rat myocardial infarction, but did not alter cardiac contractile responses to β-adrenergic stim</b><b>ulation </b>

“…HGF has been reported to enhance angiogenesis by stimulating migration and proliferation of endothelial cells and inhibiting their apoptosis (21). Cultured ASCs secreted both HGF and VEGF as reported previously (12). Both HGF and VEGF secreted by ASC sheets may play a pivotal role for angiogenesis and inhibition of cell apoptosis in MI hearts.…”

Multipotent adult progenitor cells sustain function of ischemic limbs in mice

“…Although some earlier studies have suggested that grafted cells directly contribute to a much greater degree to vessels and/or tissue in ischemia models (40,41), recent studies have demonstrated that direct contribution is minimal (9), or even absent (11,42), and that grafted cells improve vascularization via trophic effects (8,11). In our study, it is highly likely that trophic factors secreted by the long-term engrafted mMAPC-U, such as VEGF and IGF-1, contributed to the improved perfusion and limb function seen in mMAPC-U-treated animals.…”

“…Several cell types, including BM cells (BMCs), ES cells, mesenchymal stem cells (MSCs), skeletal myoblasts (SkMBs), umbilical cord or peripheral blood cells, adipose tissue-derived stem cells (ADSCs), and endothelial progenitor cells (EPCs), have been tested for their effect on restoring blood supply and/or muscle function in ischemic limbs (6)(7)(8)(9)(10)(11)(12)(13). Despite encouraging results from preclinical and small uncontrolled clinical trials (14,15), many questions concerning stem cell-based therapy remain to be answered prior to its widespread use.…”

The Regenerative Medicine Laboratory: Facilitating Stem Cell Therapy for Equine Disease

“…Bone marrow (BM)-derived MSCs effectively migrate towards and enhance the healing processes that follow cardiac infarction and hind limb ischemia, both of which are characterized by a hypoxic gradient [14][15][16]. Although there is controversy regarding the effects of low oxygen tension on MSC survival, it appears that hypoxic conditions (1%-3% O 2 ) may be beneficial, as this oxygen tension is more similar to the physiologic niche of MSCs in the bone marrow (2%-7% O 2 ) [10].…”