Depression of progenitor cell function by advanced glycation endproducts (AGEs): potential relevance for impaired angiogenesis in advanced age and diabetes.
Diabetes and ageing induce reduction and dysfunction of vascular progenitor cells. Advanced glycation endproducts (AGEs) accumulate in diabetes and ageing. We investigated the influence of AGEs on function of CD34 progenitor cells. CD34 cells were co-cultured with HUVECs in a three-dimensional spheroid assay. Sprout length growth and incorporation of CD34 cells into the sprouts were analyzed under 2, 20 or 200 microg/ml AGEs. AGE-receptor expression, MAP-kinase signal transduction and apoptosis were analyzed using PCR, Western blotting and flow cytometry. In the spheroid assay, AGEs concentration-dependently cause a reduction of sprout length growth by 6+/-6 to 32+/-6% and an attenuation of progenitor cells incorporation into the sprouting endothelium by up to 43+/-6%. This functional impairment is accompanied by activation of CD34 cell proliferation at lower concentrations (2 or 20 microg/ml) and by apoptosis activation under 200 microg/ml AGEs. The mRNA expression of the receptors for AGEs and the AGEs-induced activation of p38 and p44/42 MAP-kinases are demonstrable in CD34 cells. This AGEs-mediated impairment of progenitor cell function identifies a new pathophysiological mechanism of disturbed vascular adaptation in diabetes or ageing and suggests that lowering AGEs in recipients of progenitor cell therapy might be beneficial for the success of this therapy.
Scheubel
Robert J
RJ
Department of Cardiothoracic Surgery, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany. robert.scheubel@medizin.uni-halle.de
Kahrstedt
Simone
S
Weber
Holger
H
Holtz
Juergen
J
Friedrich
Ivar
I
Borgermann
Jochen
J
Silber
Rolf-Edgar
RE
Simm
Andreas
A
D000375:Aging / Q000502:physiology*; D018952:Antigens, CD34 / Q000097:blood; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D003925:Diabetic Angiopathies / Q000503:physiopathology; D042783:Endothelial Cells / Q000166:cytology; D004730:Endothelium, Vascular / Q000166:cytology; D004789:Enzyme Activation / Q000187:drug effects; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000097:blood; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000097:blood; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology
D018952:Antigens, CD34; D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D020928:Mitogen-Activated Protein Kinases