Journal
ADVANCED SCIENCE
Volume 4, Issue 12, Pages -Publisher
WILEY
DOI: 10.1002/advs.201700278
Keywords
endothelial progenitor cells; exosomes; inflammation resolution; macrophage reprogramming; small-diameter tissue engineering blood vessels
Categories
Funding
- National Science Fund for Distinguished Young Scholars [31625011]
- National Key Research and Development Program [2016YFC1101100]
- National Key Research and Development Plan Young Scientists Program [2017YFA0106000]
- National Science Foundation of China [31771057]
- Training Program of the Major Research Plan of the National Natural Science Foundation of China [91439116]
- New plan of military medical science [SWH2016LHJC-03]
- Young Elite Scientists Sponsorship Program by Cast [YESS20160180]
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The transplant of small-diameter tissue engineering blood vessels (small-diameter TEBVs) (<6 mm) in vascular replacement therapy often fails because of early onset thrombosis and long-standing chronic inflammation. The specific inflammation state involved in small-diameter TEBVs transplants remains unclear, and whether promoting inflammation resolution would be useful for small-diameter TEBVs therapy need study. The neural protuberant orientation factor 1 (Netrin-1) is found present in endothelial cells of natural blood vessels and has anti-inflammatory effects. This work generates netrin-1-modified small-diameter TEBVs by using layer-by-layer self-assembly to resolve the inflammation. The results show that netrin-1 reprograms macrophages (M Phi) to assume an anti-inflammatory phenotype and promotes the infiltration and subsequent efflux of M Phi from inflamed sites over time, which improves the local microenvironment and the function of early homing endothelial progenitor cells (EPCs). Small-diameter TEBVs modified by netrin-1 achieve endothelialization after 30 d and retain patency at 14 months. These findings suggest that promoting the resolution of inflammation in time is necessary to induce endothelialization of small-diameter TEBVs and prevent early thrombosis and problems associated with chronic inflammation. Furthermore, this work finds that the M Phi-derived exosomes can target and regulate EPCs, which may serve as a useful treatment for other inflammatory diseases.
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