Long-term diabetes impairs repopulation of hematopoietic progenitor cells and dysregulates the cytokine expression in the bone marrow microenvironment in mice

Abstract

Diabetes is characterized by a chronic stage of hyperglycemia associated with endothelial progenitor cell dysfunction and reduced neovascularization in response to tissue ischemia. The underlying mechanisms are not entirely clear. The bone marrow niches provide the essential microenvironment for maintenance of stem cell function in the bone marrow. A disturbed stem cell niche might lead to stem cell dysfunction, thereby, impairing progenitor cell-dependent vascular repair. Therefore, we investigated the effects of streptozotocin-induced diabetes on the bone marrow stem cell niches and stem cell function in mice. Here, we show that long-term diabetes induced a reduction in Lin⁻Sca-1(+)c-kit(+) hematopoietic progenitor cells and reduced the repopulation capacity in a competitive engraftment experiment. Consistently, the expression of Bmi1, which prevents hematopoietic progenitor cell senescence, was significantly reduced in diabetic bone marrow cells. To address the mechanism underlying the progenitor cell dysfunction, we analyzed the composition of the stem cell niche and the cytokine environment. Although the morphology of the vascular and endosteal niche was not affected by diabetes, diabetic mice showed a significant deterioration of cytokine expression patterns in the bone marrow. In summary, these data indicate that diabetes imposes a long-term effect on the stem cell niche and affects important hematopoietic progenitor cell functions in mice.

Mobilization of very small embryonic-like stem cells in acute coronary syndromes and stroke

“…Importantly, the presence of diabetes mellitus is associated with reduced number and function, as well as increased senescence, of stem cells. We found that in patients with acute MI and diabetes the mobilization of VSELs was impaired as compared to non-diabetics [26]. We also demonstrated that in patients with acute MI and reduced LVEF the number of circulating VSELs is reduced and negatively correlated with LVEF and troponin levels.…”

Microparticles in Angiogenesis

“…29 Recently, it has been shown that long-term diabetes not only impairs repopulation of hematopoietic progenitor cells but also dysregulates the cytokine expression in the bone marrow microenvironment in mice, suggesting that diabetes alters the stem cell niche. 30 Consequently, the improvement of failed functions of endothelial mature cells and EPCs during diabetes represents the goal of future therapeutic approaches.…”

Reactive Oxygen Species Adversely Impacts Bone Marrow Microenvironment in Diabetes

“…Altogether, these data suggest that the hypo-perfusion caused by contraction of the vascular niche is a major determinant of stem cell reduction in BM of diabetic mice. However, in a similar study conducted by Orlandi et al in C57BL/6 STZ-induced diabetic mice, no microvascular rarefaction was observed, probably due to the different mouse strain analyzed and shorter duration of DM (80).…”