Abstract 627: Pro-Angiogenic Properties are Impaired in Bone Marrow (BM)-Derived Stem or Progenitor Cells in Diabetes and Diabetic Hindlimb Ischemia was Effectively Repaired by Non-Diabetic Stem or Progenitor Cells
Background: Recent studies reported that angiogenesis and endothelial progenitor cells (EPCs) were dysfunctional in diabetes (DM). However, there have been no investigations on the pro-angiogenic characteristics of BM-derived cells in diabetes. Accordingly, we investigated angiogenic defects in BM-derived mononuclear cells (BM-MNCs), EPCs and mesenchymal stem cells (MSCs) and sought to determine whether hindlimb ischemia can be repaired by non-DM cells.
Method & Results: Studies were performed with C57Bl mice 3 months after the induction of diabetes with streptozotocin. Gene profiling analysis with Angiogenesis Microarray Kit (GEArray) and real-time RT-PCR showed that multiple angiogenic factors were significantly down-regulated in DM cells compared to non-DM control cells (Table 1⇓). We also compared cell functions between DM and non-DM cells. DM-EPCs revealed decreased adhesion to laminin (non-DM vs DM, 78 vs 40/mm2, P<0.05) and vitronectin(320 vs 140/mm2, P<0.05), decreased migration to VEGF-A (210 vs 85/mm2, P<0.05), and decreased tube length in Matrigel (1650 vs 610μm, P<0.05) compared to non-DM EPCs. DM-MSCs showed decreased migration to VEGF-A compared to non-DM MSCs (420 vs 154/mm2, P<0.05). Transplantation of non-DM EPCs (N-E) or MSCs(N-M) into DM hindlimb ischemia(HLI) showed significantly higher blood flow (N-E, N-M vs Saline, 0.62, 0.60 vs 0.38, P<0.05), capillary density (91, 84 vs 60/HPF), Ki67 positive cells (8.2, 7.3 vs 2.9/HPF, P<0.05) compared to the saline injected group at 2 weeks. RT-PCR demonstrated higher expression of VEGF-A, HIF-1a, FGF-2, PlGF-2 in the EPC group (all P<0.05) and VEGF-A, HIF-1a in the MSC group (all P<0.05) compared to the saline group.
Conclusion: Pro-angiogenic properties of BM-derived stem or progenitor cells were impaired in diabetes. Non-diabetic EPCs and MSCs could effectively repair diabetic HLI to a similar degree by inducing neovascularization although their angiogenic spectrum was different.