Advanced Glycation Endproducts Impair Endothelial Progenitor Cell Migration and Homing via Syndecan 4 Shedding.
Endothelial progenitor cells (EPCs) are a subtype of bone marrow-derived progenitor cells. Stromal cell-derived factor 1 (SDF-1)-mediated EPC mobilization from bone marrow to areas of ischemia plays an important role in angiogenesis. Previous studies have reported that advanced glycation endproducts (AGEs), which are important mediators of diabetes-related vascular pathology, may impair EPC migration and homing, but the mechanism is unclear. Syndecan-4 (synd4) is a ubiquitous heparan sulfate proteoglycan receptor on the cell surface, involved in SDF-1-dependent cell migration. The extracellular domain of synd4 (ext-synd4) is shed in the context of acute inflammation, but the shedding of ext-synd4 in response to AGEs is undefined. Here we investigated changes in ext-synd4 on EPCs in response to AGEs, focusing on the influence of impaired synd4 signaling on EPC migration and homing. We found decreased full length and increased residue of synd4 in cells incubated with AGEs, with concomitant increase in the soluble fragment of ext-synd4 in the cell medium. EPCs from patients with type 2 diabetes expressed less ext-synd4 as assessed by Western blotting. Flow cytometry analysis showed less ext-synd4 on circulating CD34+peripheral blood mononuclear cells, of which EPCs form a subgroup. We then explored the role of synd4 in EPC migration and homing. Impaired migration of synd4-deficient EPCs was observed by a 2D-chemotaxis slide. Furthermore, poor homing of synd4-/- EPCs was observed in a mouse model of lower limb ischemia. This study demonstrates that the shedding of synd4 from EPCs plays a key role in AGE-mediated dysfunction of EPC migration and homing. Stem Cells 2017;35:522-531.
Department of Cardiology, Drum Tower Hospital, Nanjing University Medical School, Nanjing, China.
Jun
J
Xie
Department of Cardiology, Drum Tower Hospital, Nanjing University Medical School, Nanjing, China.
Ran
R
Li
Department of Cardiology, Drum Tower Hospital, Nanjing University Medical School, Nanjing, China.
Han
H
Wu
Department of Cardiology, Drum Tower Hospital, Nanjing University Medical School, Nanjing, China.
Jianzhou
J
Chen
Department of Cardiology, Drum Tower Hospital, Nanjing University Medical School, Nanjing, China.
Guannan
G
Li
Department of Cardiology, Drum Tower Hospital, Nanjing University Medical School, Nanjing, China.
Qinhua
Q
Chen
Department of Cardiology, Drum Tower Hospital, Nanjing University Medical School, Nanjing, China.
Zhonghai
Z
Wei
Department of Cardiology, Drum Tower Hospital, Nanjing University Medical School, Nanjing, China.
Guixin
G
He
Department of Cardiology, Drum Tower Hospital, Nanjing University Medical School, Nanjing, China.
Lian
L
Wang
Department of Clinical Pharmacology, Cardiovascular Division, King's College London, London, United Kingdom.
Albert
A
Ferro
Department of Cardiology, Drum Tower Hospital, Nanjing University Medical School, Nanjing, China.
Biao
B
Xu
D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology; D066026:Endothelial Progenitor Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D000072417:Protein Domains; D017382:Reactive Oxygen Species / Q000378:metabolism; D053671:Syndecan-4 / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*
D000951:Antigens, Neoplasm; D017127:Glycation End Products, Advanced; D017382:Reactive Oxygen Species; D053671:Syndecan-4; C498978:MOK protein, human; D020928:Mitogen-Activated Protein Kinases
Advanced glycation endproducts; Chronic inflammation; Endothelial progenitor cells; Homing; Proteoglycans