Autologous Bone Marrow Cell Therapy and Metabolic Intervention in Ischemia-Induced Angiogenesis in the Diabetic Mouse Hindlimb

Abstract

Peripheral arterial disease (PAD) is a major health problem especially when associated to diabetes. Administration of autologous bone marrow cells (BMC) is emerging as a novel intervention to induce therapeutic angiogenesis in experimental ischemic limb models and in patients with PAD. Since tissue ischemia and diabetes are associated with an overwhelming generation of oxygen radicals and detrimental effects due to formation of glycosylation end-products, metabolic intervention with antioxidants and L-arginine can confer beneficial effects beyond those achieved by BMC alone. The effects of cotreatment with intravenous BMCs and metabolic vascular protection (1.0% vitamin E, 0.05% vitamin C, and 6% L-arginine) were examined in the ischemic hindlimb of diabetic and non diabetic mice. BMC therapy increased blood flow and capillary densities and Ki67 proliferative marker, and decreased interstitial fibrosis. This effect was amplified by metabolic cotreatment, an intervention inducing vascular protection, at least in part, through the nitric oxide pathway, reduction of systemic oxidative stress, and macrophage activation.

Long-term effects of repeated autologous transplantation of bone marrow cells in patients affected by peripheral arterial disease

“…[2][3][4] Preclinical studies have established that implantation of bone marrow-mononuclear cells (BM-MNC) into ischemic limbs increases collateral vessel formation in experimental models of hind limb ischemia. [5][6][7][8] In patients affected by limb ischemia, local intramuscular autologous bone marrow cell therapy has shown encouraging results with consistent revascularization of affected limbs. 9,10 A recent study showed that combined intra-arterial and intramuscular transplantation of autologous mononuclear bone marrow stem cells was a therapeutic option for patients with severe PAD.…”

Superoxide induced by a high-glucose concentration attenuates production of angiogenic growth factors in hypoxic mouse mesenchymal stem cells

“…Early studies indicated that the ability of transplanted bone marrow cells (BMCs) to promote neovascularization in the ischemic hindlimb is attenuated in diabetic animal models (Hirata et al 2003, Tamarat et al 2004, Sica et al 2006. Li et al (2006) showed that VEGF production and therapeutic angiogenesis induced by BMCs taken from obese diabetic rats are significantly lower than those of BMCs taken from control rats.…”

Stem Cell Transplantation for the Treatment of Peripheral Arterial Disease

“…This effect was amplified by metabolic vasculoprotective treatment. The latter had by itself no effect on capillary density, but could reduce interstitial fibrosis in non-diabetic mice [30]. One year later, Jeon et al [31] examined whether the angiogenic efficacy of a combination of two angiogenic strategies (EPC mobilization with G-CSF and BMMNC transplantation) is superior to either strategy alone in the mouse ischaemic hindlimb.…”

“…It was concluded that G-CSF and BMNCs combination could emerge as a helpful therapeutic approach to restore blood flow [29]. Sica et al [30] explored the effect of intravenous BMC administration and concurrent metabolic vascular protection (1.0% vitamin E, 0.05% vitamin C, and 6% L-arginine) in the ischaemic hindlimb of diabetic and non-diabetic mice. In both mice, BMC treatment increased blood flow and capillary density and decreased interstitial fibrosis [30].…”

“…Sica et al [30] explored the effect of intravenous BMC administration and concurrent metabolic vascular protection (1.0% vitamin E, 0.05% vitamin C, and 6% L-arginine) in the ischaemic hindlimb of diabetic and non-diabetic mice. In both mice, BMC treatment increased blood flow and capillary density and decreased interstitial fibrosis [30]. This effect was amplified by metabolic vasculoprotective treatment.…”