BACKGROUND: Chronic kidney disease (CKD) is associated with increased risk for cardiovascular diseases (CVD). We hypothesized that inadequate angiogenic response in uremic patients could result from dysfunction of bone marrow-derived stromal cells [mesenchymal stem cells (MSCs)]. METHODS: We investigated whether MSCs are functionally competent in uremia induced by partial kidney ablation in C57Bl/6J mice. RESULTS: Uremic MSCs showed decreased expression of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)1 and stromal cell-derived factor (SDF)-1α, increased cellular senescence, decreased proliferation, defects in migration in response to VEGF and SDF-1α and in vitro tube formation. Interestingly, the expression of fibroblast-specific protein-1 was higher in uremic MSCs. Uremia decreased hypoxia-inducible factor-1α, VEGF and VEGFR1 expression under hypoxia and Akt phosphorylation in both basal and VEGF-stimulated states. A diminished mitogenic effect on endothelial proliferation was observed in conditioned media from uremic MSCs. In addition, intravital microscopic analysis showed decreased angiogenesis in uremic MSCs. CONCLUSION: These results clearly demonstrate the functional incompetence in MSCs under uremic conditions and may significantly contribute to the disproportionately high risk for CVD in patients with CKD.
BACKGROUND:Chronic kidney disease (CKD) is associated with increased risk for cardiovascular diseases (CVD). We hypothesized that inadequate angiogenic response in uremic patients could result from dysfunction of bone marrow-derived stromal cells [mesenchymal stem cells (MSCs)]. METHODS: We investigated whether MSCs are functionally competent in uremia induced by partial kidney ablation in C57Bl/6J mice. RESULTS: Uremic MSCs showed decreased expression of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)1 and stromal cell-derived factor (SDF)-1α, increased cellular senescence, decreased proliferation, defects in migration in response to VEGF and SDF-1α and in vitro tube formation. Interestingly, the expression of fibroblast-specific protein-1 was higher in uremic MSCs. Uremia decreased hypoxia-inducible factor-1α, VEGF and VEGFR1 expression under hypoxia and Akt phosphorylation in both basal and VEGF-stimulated states. A diminished mitogenic effect on endothelial proliferation was observed in conditioned media from uremic MSCs. In addition, intravital microscopic analysis showed decreased angiogenesis in uremic MSCs. CONCLUSION: These results clearly demonstrate the functional incompetence in MSCs under uremic conditions and may significantly contribute to the disproportionately high risk for CVD in patients with CKD.
Authors: Chetan V Jawale; Kritika Ramani; De-Dong Li; Bianca M Coleman; Rohan S Oberoi; Saran Kupul; Li Lin; Jigar V Desai; Greg M Delgoffe; Michail S Lionakis; Filitsa H Bender; Alexander J Prokopienko; Thomas D Nolin; Sarah L Gaffen; Partha S Biswas Journal: Sci Transl Med Date: 2020-06-17 Impact factor: 17.956
Authors: Moustafa Sayed; Christopher A Drummond; Kaleigh L Evans; Steven T Haller; Jiang Liu; Zijian Xie; Jiang Tian Journal: Stem Cell Res Date: 2014-04-13 Impact factor: 2.020
Authors: Shuanhu Zhou; Julie Glowacki; Sung Won Kim; Jochen Hahne; Shuo Geng; Stefan M Mueller; Longxiang Shen; Ilan Bleiberg; Meryl S LeBoff Journal: J Bone Miner Res Date: 2012-09 Impact factor: 6.741