Therapeutic Effect of Human Adipose‐Derived Stromal Cells Cluster in Rat Hind‐Limb Ischemia

Abstract

We investigated whether transplantation of three-dimensional cell masses (3DCM) of human adipose-derived stromal cells (hASCs) cultured on a basic fibroblast growth factor-immobilized substrate improved hind limb functional recovery by stimulating angiogenesis in an immune-competent rat ischemic limb model. In vitro experiments confirmed that cells within 3DCMs differentiate toward the endothelial lineage one day after culture in normal medium. The therapeutic effect of 3DCMs was evaluated by transplanting hASCs, phosphate-buffered saline alone, and the 3DCM into rat ischemic hind limbs. Blood flow was enhanced in the ischemic hind limb in the 3DCM-injected group compared with the other groups. The ratio of human nuclear antigen (HNA) and hVEGF-positive cells was significantly higher in the 3DCM-injected group compared to hASC-injected group. Human VEGF was observed in most HNA-positive cells. Many hCD31 and hSMA-positive cells were observed in vessel-like structures in the 3DCM-injected group. The 3DCM transplantation improved cell retention and angiogenic effects compared with ASC transplantation. These findings suggest that transplantation of 3DCMs may be an effective stem cell therapy for hind limb ischemia.

TGFβ signalling pathway regulates angiogenesis by endothelial cells, in an adipose‐derived stromal cell/endothelial cell co‐culture 3D gel model

“…Previous studies have shown that ASCs promote survival, proliferation, endothelial tubulogenesis and vascularization of ECs and stable vascular assembly . Combination of ASCs and ECs further promote formation of vascular networks . In addition, co‐implantation of mesenchymal stromal cells ((MSCs), similar to ASCs) and endothelial cells, markedly expedite formation of functional microvascular beds and provides possible methods for cell‐based revascularization therapies to treat various diseases, such as in the peripheral vasculature and ischaemic heart disease .…”

Self-organized insulin-producing β-cells differentiated from human omentum-derived stem cells and their in vivo therapeutic potential

“…This is in agreement with previously reported studies that have highlighted the important role of vascularization and angiogenesis around β-cells in promoting insulin secretion and enhancing in vivo β-cell function [ 66 , 67 ]. Furthermore, our previous study demonstrated that the formation of spheroids using human adipose-derived MSCs (hASCs) on the MBP-FGF2 cell culture platform upregulated in vivo engraftment by promoting the secretion of various angiogenic factors, including interleukin-8 (IL-8), fibroblast growth factors (FGFs), vascular endothelial growth factor (VEGF), and platelet-derived growth factors (PDGFs) [ 50 , 68 , 69 ]. When these FGF2-primed hASC spheroids were transplanted into an ischemic mouse model, cells could robustly secrete IL-8 through the FGFR1/JNK/NF-κB signaling cascade and contribute to therapeutic angiogenesis.…”

Combinatorial therapy with three-dimensionally cultured adipose-derived stromal cells and self-assembling peptides to enhance angiogenesis and preserve cardiac function in infarcted hearts

“…Previously, three‐dimensional cell masses (3DCMs) were developed that were capable of differentiating into endothelial cells (ECs) and releasing angiogenic factors for the treatment of ischaemic diseases (Kang et al ., ; Park et al ., ). A spheroid‐type of 3DCM (1.2 mm diameter) was obtained by culturing human ASCs (hASCs) on a fibroblast growth factor‐2 (FGF2)‐immobilized substrate for 24 h. Previous studies demonstrated the therapeutic potential of 3DCMs for the treatment of hind‐limb ischemia in mouse (Park et al ., 2014a,b) and rat (Park et al ., ) and MI in a rat (Kim et al ., ). Survival and retention ratios of transplanted cells were higher in the group injected with 3DCMs than in the group injected with hASCs.…”