Glucocorticoid Impaired the Wound Healing Ability of Endothelial Progenitor Cells by Reducing the Expression of CXCR4 in the PGE2 Pathway.
Glucocorticoid Impaired the Wound Healing Ability of Endothelial Progenitor Cells by Reducing the Expression of CXCR4 in the PGE2 Pathway.
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DOI：
10.3389/fmed.2018.00276
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发表时间：
2018
影响因子：
3.9
通讯作者：
Ohneda O
中科院分区：
文献类型：
--
作者：
Carolina E;Kato T;Khanh VC;Moriguchi K;Yamashita T;Takeuchi K;Hamada H;Ohneda O
背景：内皮祖细胞（EPCs）可用于缺血性疾病的细胞基础治疗，由于其新生血管的潜力。糖皮质激素（GCs）作为强抗炎药物已被广泛应用。然而，尽管有有益的作用，但以GC为基础的治疗通常会出现副作用，例如损害伤口愈合，并且GC治疗对EPCs伤口愈合功能的影响尚不清楚。方法：研究GC处理对EPCs特性及创面愈合功能的影响。结果：GC处理降低了EPCs的增殖能力。此外，CXCR4的表达显著受损，抑制了EPCs的迁移。一项皮瓣小鼠模型的移植研究显示，gc处理的EPCs对损伤部位的归巢能力较差，招募炎症细胞的活性较低，导致伤口愈合功能障碍。前列腺素E2 （PGE2）合成酶、环氧化酶（COX2）和微体PGE2合成酶1 （mPEGS1）的损伤参与了gc诱导的EPCs中CXCR4表达的损伤。PGE2可恢复CXCR4的表达，恢复gc处理的EPCs的迁移能力。此外，我们还发现激活PI3K/AKT通路的PGE2信号在gc作用下参与了EPCs中CXCR4的调控。此外，在缺氧条件下，在EPCs中也观察到类似的GCs的负面影响。在缺氧条件下，GCs独立破坏PGE2和HIF2α通路，从而下调EPCs中CXCR4的表达。我们的研究结果强调了GCs对EPCs特性和功能的影响，提示长期使用GCs的患者应慎重考虑使用EPCs进行自体细胞移植。
Background: Endothelial progenitor cells (EPCs) can be used to treat ischemic disease in cell-based therapy owing to their neovascularization potential. Glucocorticoids (GCs) have been widely used as strong anti-inflammatory reagents. However, despite their beneficial effects, side effects, such as impairing wound healing are commonly reported with GC-based therapy, and the effects of GC therapy on the wound healing function of EPCs are unclear. Methods: In this study, we investigated how GC treatment affects the characteristics and wound healing function of EPCs. Results: We found that GC treatment reduced the proliferative ability of EPCs. In addition, the expression of CXCR4 was dramatically impaired, which suppressed the migration of EPCs. A transplantation study in a flap mouse model revealed that GC-treated EPCs showed a poor homing ability to injured sites and a low activity for recruiting inflammatory cells, which led to wound healing dysfunction. Impairment of prostaglandin E2 (PGE2) synthases, cyclooxygenase (COX2) and microsomal PGE2 synthase 1 (mPEGS1) were identified as being involved in the GC-induced impairment of the CXCR4 expression in EPCs. Treatment with PGE2 rescued the expression of CXCR4 and restored the migration ability of GC-treated EPCs. In addition, the PGE2 signal that activated the PI3K/AKT pathway was identified to be involved in the regulation of CXCR4 in EPCs under the effects of GCs. In addition, similar negative effects of GCs were observed in EPCs under hypoxic conditions. Under hypoxic conditions, GCs independently impaired the PGE2 and HIF2α pathways, which downregulated the expression of CXCR4 in EPCs. Our findings highlighted the influences of GCs on the characteristics and functions of EPCs, suggesting that the use of EPCs for autologous cell transplantation in patients who have used GCs for a long time should be considered carefully.
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DOI：
10.2147/ccid.s50046
发表时间：
2014
期刊：
Clinical, cosmetic and investigational dermatology
影响因子：
--
作者：
Darby IA;Laverdet B;Bonté F;Desmoulière A
通讯作者：
Desmoulière A
影响因子：
15.9
作者：
Butler, JM;Guthrie, SM;Scott, EW
通讯作者：
Scott, EW
影响因子：
56.9
作者：
Asahara, T;Murohara, T;Isner, JM
通讯作者：
Isner, JM
DOI：
10.1165/ajrcmb.21.1.3396
发表时间：
1999-07-01
影响因子：
6.4
作者：
Fernandes, D;Guida, E;Stewart, AG
通讯作者：
Stewart, AG
影响因子：
7.4
作者：
Lin Y;Luo LL;Sun J;Gao W;Tian Y;Park E;Baker A;Chen J;Jiang R;Zhang J
通讯作者：
Zhang J