Abstract
Bone marrow stem cells from diabetes mellitus patients exhibit functional impairment, but the relative molecular mechanisms responsible for this impairment are poorly understood. We investigated the mechanisms responsible for diabetes-related functional impairment of bone marrow stem cells by extensively screening the expression levels of inflammatory factors, cell cycle regulating molecules, extracellular matrix molecules and adhesion molecules. Bone marrow cells were collected from type 2 diabetic (db/db) and healthy control (db/m+) mice, and c-kit+ stem cells were purified (purity>85%) for experiments. Compared with the healthy control mice, diabetic mice had significantly fewer c-kit+ stem cells, and these cells had a lower potency of endothelial differentiation; however, the production of the angiogenic growth factor VEGF did not differ between groups. A pathway-focused array showed that the c-kit+ stem cells from diabetic mice had up-regulated expression levels of many inflammatory factors, including Tlr4, Cxcl9, Il9, Tgfb1, Il4, and Tnfsf5, but no obvious change in the expression levels of cell cycle molecules. Interestingly, diabetes-related alterations of the extracellular matrix and adhesion molecules were varied; Pecam, Mmp10, Lamc1, Itgb7, Mmp9, and Timp4 were up-regulated, but Col11a1, Fn1, Admts2, and Itgav were down-regulated. Some of these changes were also confirmed at the protein level by flow cytometry analysis. In conclusion, c-kit+ bone marrow stem cells from diabetic mice exhibited an extensive enhancement of inflammatory factors and disorders of the extracellular matrix and adhesion molecules. Further intervention studies are required to determine the precise role of each molecule in the diabetes-related functional impairment of c-kit+ bone marrow stem cells.
Highlights
In the past decade, a number of studies have demonstrated that stem cells of bone marrow origin play very important roles in repairing/regenerating various organs [1,2,3,4,5,6,7], including the injured heart and vessels, through direct regeneration or indirect mechanisms [8,9,10,11]
After 7 days of culturing purified c-kit+ stem cells, we found that cells from diabetic mice had poorer attachment and expressed lower levels of vascular endothelial (VE)-cadherin when compared with cells from healthy control mice (p,0.05, Figure 1E)
If we can understand the molecular mechanisms associated with the functional impairment of bone marrow stem cells, new approaches may be found to prevent and treat these diabetes-associated complications
Summary
A number of studies have demonstrated that stem cells of bone marrow origin play very important roles in repairing/regenerating various organs [1,2,3,4,5,6,7], including the injured heart and vessels, through direct regeneration (cell differentiation/ maturation) or indirect mechanisms (paracrine effects) [8,9,10,11]. Clinical trials have attempted to treat ischemic heart diseases and peripheral arterial diseases by implanting autologous bone marrow-derived stem cells [12,13,14,15,16,17]. Some of these clinical trials have reported improvements in the clinical symptoms and regional perfusion of ischemia after treatment, but the therapeutic benefits observed were very marginal and mild, especially in patients of advanced age and those with diabetes and other diseases. Using a pathway-focused microarray, we extensively compared the expression levels of inflammatory cytokines, cell cycle regulating factors, cell adhesion molecules and extracellular matrix molecules in c-kit+ bone marrow stem cells from diabetic mice and normal healthy mice, and we attempted to further uncover the complex molecular mechanisms responsible for the diabetes-associated functional impairment of bone marrow stem cells
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