Diabetes and aging: a different phenotypic commitment of circulating and resident stem cells?

Excerpt

Atherosclerosis is a vascular disease largely attributed to chronic vascular injury, and its clinical manifestations appear more frequently in aged subjects. Accumulation of vascular smooth muscle cells in the tunica intima plays a major role in the pathogenesis of atherosclerosis. Arterial smooth muscle cells are heterogeneous even in the normal vessel wall and display more marked different phenotypes in pathological conditions. Smooth muscle cells in atherosclerotic plaques display a de-differentiated or “synthetic” phenotype compared to a “contractile” phenotype in the normal media. Aorta stiffens with age and other cardiovascular risk factors. In particular, diabetes-induced activation of the renin–angiotensin system increases the expression of angiotensin II, further increasing aortic calcification and stiffness. Thus, alterations of aortic and carotid walls in patients with diabetes were traditionally considered a sort of “accelerated aging.” In the last years, the contribution of stem cells to atherosclerosis has been highlighted. Bone marrow and peripheral blood-derived endothelial and vascular smooth muscle cell resident progenitors both contribute to vascular remodeling during atherogenetic process and aging [1]. Both circulating and resident progenitor cells have been evocated to contribute to the response of the adult arterial wall to damage. Chronic treatment with bone marrow-derived progenitor cells from young non-atherosclerotic ApoE⁻/⁻ mice prevents atherosclerosis progression in ApoE⁻/⁻ recipients despite persistent hypercholesterolemia, whereas bone marrow-derived progenitor cells from older ApoE⁻/⁻ mice with atherosclerosis were much less effective [2]. These findings suggest that the progressive bone marrow-derived progenitor cells deficit may contribute to the development of atherosclerosis. Nevertheless, atherosclerotic lesions are characterized from the increase of stem cell marker-expressing cells, and macroscopically normal aortas from human and rat aged donors show an increased number of VEGFR-1⁺ and c-kit⁺ cells in the thickened intima [3]. Also, diabetes alters the function of circulating progenitor cells. Depletion of bone marrow-derived angiogenic cell populations may further promote atherogenesis and aortic calcification in patients with diabetes mellitus [4]. In multivariable analyses, the increase in colony-forming units from endothelial progenitor cells was associated with the decrease in coronary artery and abdominal aortic calcification [5]. These changes were not associated with changes in CD34⁺ expression, suggesting that a decreased angiogenic potential contributes to the development of human atherosclerosis. Moreover, decreasing colony-forming capacity associated with the progressive increase of calcification scores [5]. Recently, it has been reported that diabetes mellitus patients had significantly higher expression of osteocalcin and bone alkaline phosphatase on circulating VEGFR-2⁺/CD34⁺ progenitor cells than control subjects [6]. Moreover, cultured VEGFR-2⁺/CD34⁺ cells from diabetes mellitus patients formed structures highly suggestive of calcified nodules, strongly suggesting that circulating progenitor cells from diabetic patients show a drift toward a pro-calcific phenotype that may be driven by inflammatory signals in response to injury [6], similarly to that observed in non-vascular tissues [7]. Monocyte–macrophage recruitment is a crucial step for a correct angiogenesis, and this mechanism is mainly mediated by VEGFR-1, that favors the increase of vessel lumen, vessel stabilization and monocyte–macrophage infiltration and counteracts pathological angiogenesis stimulated from PlGF-mutated variants that not bind VEGFR-1 [8, 9]. These findings suggest that aging and diabetes share the decrease of circulating endothelial cells with potential angiogenic/reparative properties, but in addition, diabetes associates a conversion toward a pro-calcific phenotype, whereas with aging stem cells with a synthetic VEGFR-1⁺ myocitic phenotype prevail and contribute to aortic myointimal thickening and to vascular angiogenetic or healing processes [10, 11]. Although these findings support the divergent phenotypic conversion of circulating precursor cells, further studies are needed to verify whether also aortic resident stem cells are similarly modified in their differentiative capacities in diabetic patients. …