Vascular stem cells in diabetic complications: evidence for a role in the pathogenesis and the therapeutic promise

Abstract

Long standing diabetes leads to structural and functional alterations in both the micro- and the macro-vasculature. Vascular endothelial cells (ECs) are the primary target of the hyperglycemia-induced adverse effects. Vascular stem cells that give rise to endothelial progenitor cells (EPCs) and mesenchymal progenitor cells (MPCs) represent an attractive target for cell therapy for diabetic patients. A number of studies have reported EPC dysfunction as a novel participant in the culmination of the diabetic complications. The controversy behind the identity of EPCs and the similarity between these progenitor cells to hematopoietic cells has led to conflicting results. MPCs, on the other hand, have not been examined for a potential role in the pathogenesis of the complications. These multipotent cells, however, do show a therapeutic role. In this article, we summarize the vascular changes that occur in diabetic complications highlighting some of the common features, the key findings that illustrate an important role of vascular stem cells (VSCs) in the pathogenesis of chronic diabetic complications, and provide mechanisms by which these cells can be used for therapy.

Diabetic microangiopathy: Pathogenetic insights and novel therapeutic approaches

“…Several studies have shown that exposure to high levels of glucose leads to a series of biochemical, structural and functional changes in mature vascular ECs and VSMCs, which can be summarized as follows [2,17]: 1) biochemical changes: accumulation of advanced glycation endproducts (AGEs); increased production of the procoagulant protein von Willebrand Factor (VWF); increased apoptosis, induced by increased oxidative stress; increase in intracellular Ca 2+ ; mitochondrial dysfunction; changes in intracellular metabolism of fatty acid; activation of the mitogen-activated protein kinase (MAPK) signaling pathways; and reduced phosphorylation/activation of protein kinase B (also known as Akt); 2) structural changes: increased production of extracellular matrix proteins, collagen and fibronectin, and of related enzymes (i.e., matrix metalloproteinases, MMPs); 3) functional changes: reduction in cell proliferation and migration; impairment of endothelium-dependent vasodilatation, linked to decreased production of vasodilators and increased production of vasoconstrictors; induction of ischemia and neo-angiogenesis [17]. In human retinal ECs, both the poly-ADP-ribose polymerase (PARP) and the nuclear factor-kappa B (NF-κB) signaling play central roles, as described below.…”

Pathophysiological role of enhanced bone marrow adipogenesis in diabetic complications

“…6 These secondary complications stem from the effects of sustained levels of hyperglycemia on the vascular system of select organs. 7,8 Vascular endothelial cells lining blood vessel walls are the first to encounter high levels of circulating glucose. [7][8][9] Sustained uptake of glucose by vessel endothelial cells results in impaired cellular function, resulting in microvascular and macrovascular changes.…”

“…7,8 Vascular endothelial cells lining blood vessel walls are the first to encounter high levels of circulating glucose. [7][8][9] Sustained uptake of glucose by vessel endothelial cells results in impaired cellular function, resulting in microvascular and macrovascular changes. 8,9 One of the earliest defects apparent in target organs of diabetic complications is a diminished capacity for vasodilation due to the unbalanced production of vasodilators and vasoconstrictors.…”

“…8,9 One of the earliest defects apparent in target organs of diabetic complications is a diminished capacity for vasodilation due to the unbalanced production of vasodilators and vasoconstrictors. [7][8][9] Decreased levels of the vasodilator nitric oxide, coupled increased production of the powerful vasoconstrictor endothelin-1, results in impaired vasoregulation. This functional alteration is accompanied by sustained structural remodelling of the vessels in target organs manifesting as retinopathy, nephropathy, neuropathy, cardiomyopathy, and accelerated atherosclerosis.…”

“…This functional alteration is accompanied by sustained structural remodelling of the vessels in target organs manifesting as retinopathy, nephropathy, neuropathy, cardiomyopathy, and accelerated atherosclerosis. [7][8][9] Initiation as well as the progression of these complications also entails an impaired repair/regenerative mechanism. 10,11 Vascular repair is largely dependent on the proliferation, mobilization and differentiation of bone marrow-derived progenitor cells.…”