☆ 4.6 Article

Bone Marrow Alterations and Lower Endothelial Progenitor Cell Numbers in Critical Limb Ischemia Patients

PLOS ONE (2013)

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PLOS ONE

卷 8, 期 1, 页码 -

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PUBLIC LIBRARY SCIENCE

DOI: 10.1371/journal.pone.0055592

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Multidisciplinary Sciences

资金

Stichting Vrienden UMC Utrecht of Dirkzwager-Assink foundation (The Netherlands) [CS 06.007]
Dutch Heart Foundation (The Netherlands) [2008B094]
the Netherlands Organisation for Scientific Research (The Netherlands) [116001026]
foundation De Drie Lichten (The Netherlands) [10/06]
the Netherlands Organisation for Scientific Research (NWO) (The Netherlands) [016.096.359]

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摘要

Background: Critical limb ischemia (CLI) is characterized by lower extremity artery obstruction and a largely unexplained impaired ischemic neovascularization response. Bone marrow (BM) derived endothelial progenitor cells (EPC) contribute to neovascularization. We hypothesize that reduced levels and function of circulating progenitor cells and alterations in the BM contribute to impaired neovascularization in CLI. Methods: Levels of primitive (CD34(+) and CD133(+)) progenitors and CD34(+) KDR+ EPC were analyzed using flow cytometry in blood and BM from 101 CLI patients in the JUVENTAS-trial (NCT00371371) and healthy controls. Blood levels of markers for endothelial injury (sE-selectin, sICAM-1, sVCAM-1, and thrombomodulin), and progenitor cell mobilizing and inflammatory factors were assessed by conventional and multiplex ELISA. BM levels and activity of the EPC mobilizing protease MMP-9 were assessed by ELISA and zymography. Circulating angiogenic cells (CAC) were cultured and their paracrine function was assessed. Results: Endothelial injury markers were higher in CLI (P<0.01). CLI patients had higher levels of VEGF, SDF-1 alpha, SCF, G-CSF (P<0.05) and of IL-6, IL-8 and IP-10 (P<0.05). Circulating EPC and BM CD34(+) cells (P<0.05), lymphocytic expression of CXCR4 and CD26 in BM (P<0.05), and BM levels and activity of MMP-9 (P<0.01) were lower in CLI. Multivariate regression analysis showed an inverse association between IL-6 and BM CD34(+) cell levels (P = 0.007). CAC from CLI patients had reduced paracrine function (P<0.0001). Conclusion: CLI patients have reduced levels of circulating EPC, despite profound endothelial injury and an EPC mobilizing response. Moreover, CLI patients have lower BM CD34(+)-cell levels, which were inversely associated with the inflammatory marker IL-6, and lower BM MMP-9 levels and activity. The results of this study suggest that inflammation-induced BM exhaustion and a disturbed progenitor cell mobilization response due to reduced levels and activity of MMP-9 in the BM and alterations in the SDF-1 alpha/CXCR4 interaction contribute to the attenuated neovascularization in CLI patients.

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Multibiofunctional TFEB-engineered endothelial progenitor cell-derived extracellular vesicles/hydrogel system for rescuing critical limb ischemia

Chen Zhao, Zheng Xing, Xinbo Wei, Guoyu Liao, Depeng Yang, Haifeng Liu, Yubo Fan

Summary: Critical limb ischemia (CLI) is the terminal stage of peripheral arterial disease (PAD), and it often leads to high risk of amputations and deaths. In this study, a multifunctional engineered-extracellular vesicles (EVs)/hydrogel system was developed for promoting angiogenesis and protecting ischemic muscle tissue without surgery. The results showed that TFEB-EVs/FPD significantly enhanced neovascularization, alleviated muscle damage, and protected the limb function of CLI mice.

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