High Levels of Pigment Epithelium–Derived Factor in Diabetes Impair Wound Healing Through Suppression of Wnt Signaling

Qi, Weiwei; Yang, Chuan; Dai, Zhi; Che, Di; Feng, Juan; Mao, Yuling; Cheng, Rui; Wang, Zhongxiao; He, Xianghui; Zhou, Ti; Gu, Xiaoqiong; Li, Yan; Yang, Xia; Xing, Jian; Gao, Guoquan

doi:10.2337/db14-1111

Cited by 95 publications

(81 citation statements)

References 51 publications

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“…A recent study found that circulating PEDF was higher in diabetic patients with foot ulcers (45). Neutralizing systemic PEDF via anti-PEDF antibody perfusion or in PEDF knockout mice improved healing rates coincident with higher wound angiogenesis, whereas systemic overexpression of PEDF slowed healing coincident with lower wound angiogenesis in diabetic mice.…”

Section: Discussionmentioning

confidence: 97%

“…PEDF is expressed in many mammalian tissues (21,58) and exists at high levels in unwounded human dermis (23,38) and in the blood (42). While various tumors (58) and ischemic hearts (49) express relatively low levels of PEDF, a recent study showed that high systemic levels of PEDF may be etiologic for impaired healing in diabetics due to excessive antiangiogenesis (45). PEDF is produced by quiescent FBs (15,44) in normoxic conditions (49) and by keratinocytes (KCs) (14), and it is readily secreted into the ECM.…”

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confidence: 99%

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Pigment epithelium-derived factor as a multifunctional regulator of wound healing

Wietecha

Król

Michalczyk

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Wietecha MS, Król MJ, Michalczyk ER, Chen L, Gettins PG, DiPietro LA. Pigment epithelium-derived factor as a multifunctional regulator of wound healing. Am J Physiol Heart Circ Physiol 309: H812-H826, 2015. First published July 10, 2015; doi:10.1152/ajpheart.00153.2015.-During dermal wound repair, hypoxia-driven proliferation results in dense but highly permeable, disorganized microvascular networks, similar to those in solid tumors. Concurrently, activated dermal fibroblasts generate an angiopermissive, provisional extracellular matrix (ECM). Unlike cancers, wounds naturally resolve via blood vessel regression and ECM maturation, which are essential for reestablishing tissue homeostasis. Mechanisms guiding wound resolution are poorly understood; one candidate regulator is pigment epithelium-derived factor (PEDF), a secreted glycoprotein. PEDF is a potent antiangiogenic in models of pathological angiogenesis and a promising cancer and cardiovascular disease therapeutic, but little is known about its physiological function. To examine the roles of PEDF in physiological wound repair, we used a reproducible model of excisional skin wound healing in BALB/c mice. We show that PEDF is abundant in unwounded and healing skin, is produced primarily by dermal fibroblasts, binds to resident microvascular endothelial cells, and accumulates in dermal ECM and epidermis. PEDF transcript and protein levels were low during the inflammatory and proliferative phases of healing but increased in quantity and colocalization with microvasculature during wound resolution. Local antibody inhibition of endogenous PEDF delayed vessel regression and collagen maturation during the remodeling phase. Treatment of wounds with intradermal injections of exogenous, recombinant PEDF inhibited nascent angiogenesis by repressing endothelial proliferation, promoted vascular integrity and function, and increased collagen maturity. These results demonstrate that PEDF contributes to the resolution of healing wounds by causing regression of immature blood vessels and stimulating maturation of the vascular microenvironment, thus promoting a return to tissue homeostasis after injury.

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Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 99%

Pigment epithelium-derived factor as a multifunctional regulator of wound healing

Wietecha

Król

Michalczyk

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…The lifetime risk of a patient with diabetes developing a foot ulcer reaches as high as 25%, and it is believed that every 30 seconds a lower limb is lost somewhere in the world because of diabetes [2]. Angiogenesis plays an important role in skin maintenance and repair, depending on various kinds of cell participation and coordination, including endothelial precursor cells (EPCs) and endothelial cells (ECs) [3]. …”

Section: Introductionmentioning

confidence: 99%

PPARα Agonist Stimulated Angiogenesis by Improving Endothelial Precursor Cell Function Via a NLRP3 Inflammasome Pathway

Deng¹,

Han²,

Zheng³

et al. 2017

Cell Physiol Biochem

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Background: Impaired wound healing is a common complication of diabetes and is the leading cause of lower extremity amputation. Treatment with fenofibrate, a peroxisome proliferators–activated receptor α (PPARα) agonist, was associated with a lower risk of amputations, particularly minor amputations without known large-vessel diseases, probably through non-lipid mechanisms. The current study aimed to test our hypothesis that fenofibrate stimulates angiogenesis and restores endothelial precursor cell (EPC) function via inhibiting Nod-like receptor protein 3 (NLRP3) inflammasome in streptozotocin (STZ)-induced diabetic mice. Methods: Male C57BL/6 mice were randomly divided into three groups: control, STZ-induced diabetic mice and fenofibrate treated diabetic group. Wound closure was assessed by wound area and CD31 positive capillaries. Both the migration and tube formation capacities of EPCs were measured. Intracellular nitric oxide (NO) and superoxide (O₂^-) levels were determined. Activity of NLRP3 inflammasome in EPCs was assessed by measuring thioredoxin-interacting protein (TXNIP), NLRP3, and caspase-1 expression. Results: Compared with the untreated diabetic mice, wound closure and capillary densities were significantly increased in fenofibrate treated group. Fenofibrate treatment restored EPC function, increased NO production, and decreased O₂^- level in EPCs of diabetic mice. Furthermore, fenofibrate deregulated the activity of NLRP3 inflammasome by reducing TXNIP, NLRP3 and caspase-1 expression in EPCs of diabetic mice. In vitro, fenofibrate prevented high glucose induced EPC dysfunction, deregulated NLRP3 inflammasome activity. In addition, fenofibrate inhibited IL-1β expression caused by combination use of high glucose and lipopolysaccharide. Conclusion: Fenofibrate can accelerate wound healing in diabetic mice, which at least in part was mediated by improving the impaired EPC function via a NLRP3 inflammasome pathway, suggesting the significance of PPARα agonists in the treatment of diabetes.

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“…PEDF modulates target cell responses by signaling via a family of unrelated high affinity receptors. The anti-angiogenic activity of PEDF is mediated by the laminin receptor (19)(20)(21); low-density lipoprotein receptor-related protein 6 (LPR6; Wnt co-receptor) (22); and cell surface F 1 F 0 -ATP synthase (23). The macrophage stimulating (16) and neurotrophic activities (24) of PEDF are mediated by adipose mice were more than >200 mg/dL by d 7, and remained at that level thereafter ( Figure 1A).…”

Section: Induction Of Diabetesmentioning

confidence: 98%

Emetine Di-HCl Attenuates Type 1 Diabetes Mellitus in Mice

Hudson

Dancho

et al. 2016

Mol Med

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Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease characterized by β cell destruction, insulin deficiency and hyperglycemia. Activated macrophages and autoimmune T cells play a crucial role in the pathogenesis of hyperglycemia in NOD murine diabetes models, but the molecular mechanisms of macrophage activation are unknown. We recently identified pigment epithelium-derived factor (PEDF) as an adipocyte-derived factor that activates macrophages and mediates insulin resistance. Reasoning that PEDF might participate as a proinflammatory mediator in murine diabetes, we measured PEDF levels in NOD mice. PEDF levels are significantly elevated in pancreas, in parallel with pancreatic TNF levels in NOD mice. To identify experimental therapeutics, we screened 2,327 compounds in two chemical libraries (the NIH Clinical Collection and Pharmakon-1600) for leads that inhibit PEDF mediated TNF release in macrophage cultures. The lead molecule selected, "emetine" is a widely used emetic. It inhibited PEDF-mediated macrophage activation with an EC50 or 146 nmol/L. Administration of emetine to NOD mice and to C57Bl6 mice subjected to streptozotocin significantly attenuated hyperglycemia, reduced TNF levels in pancreas and attenuated insulitis. Together, these results suggest that targeting PEDF with emetine may attenuate TNF release and hyperglycemia in murine diabetes models. This suggests that further investigation of PEDF and emetine in the pathogenesis of human diabetes is warranted.

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High Levels of Pigment Epithelium–Derived Factor in Diabetes Impair Wound Healing Through Suppression of Wnt Signaling

Cited by 95 publications

References 51 publications

Pigment epithelium-derived factor as a multifunctional regulator of wound healing

Pigment epithelium-derived factor as a multifunctional regulator of wound healing

PPARα Agonist Stimulated Angiogenesis by Improving Endothelial Precursor Cell Function Via a NLRP3 Inflammasome Pathway

Emetine Di-HCl Attenuates Type 1 Diabetes Mellitus in Mice

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