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Advanced Glycation Endproducts Impair Endothelial Progenitor Cell Migration and Homing via Syndecan 4 Shedding

Research output: Contribution to journalArticlepeer-review

Jun Xie, Ran Li, Han Wu, Jianzhou Chen, Guannan Li, Qinhua Chen, Zhonghai Wei, Guixin He, Lian Wang, Albert Ferro, Biao Xu

Original languageEnglish
Pages (from-to)522-531
Number of pages10
JournalStem cells (Dayton, Ohio)
Volume35
Issue number2
Early online date24 Oct 2016
DOIs
Accepted/In press13 Jul 2016
E-pub ahead of print24 Oct 2016
Published1 Feb 2017

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Abstract

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.

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