Pigment Epithelium-Derived Factor Inhibits Lysosomal Degradation of Bcl-xL and Apoptosis in HepG2 cells

Kawaguchi, Takumi; Yamagishi, Sho‐ichi; Itou, Minoru; Okuda, K; Sumie, Shuji; Kuromatsu, Ryoko; Sakata, Masahiro; Abe, Mitsuhiko; Taniguchi, Eitaro; Koga, Hironori; Harada, Masaru; Ueno, Takato; Sata, Michio

doi:10.2353/ajpath.2010.090242

Cited by 20 publications

(23 citation statements)

References 52 publications

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“…11,15,16 Conversely, it exerts anti-apoptotic effects on neuronal or hepatoma cells by activating the nuclear factor-κB signaling cascade or inhibiting lysosomal Bcl-xL degradation, respectively. 15,16,20 It can also inhibit platelet-derived growth factor-induced VSMC proliferation and migration by blocking reactive oxygen species generation, 18 although we recently demonstrated that PEDF stimulated both proliferation and migration of retinal pigment epithelial cells in a laser-induced choroidal neovascularization model. 21 It is speculated that the elusive functions of PEDF may attribute to multiple unknown receptors, the immediate cellular state, as well as pathologic signals and factors present in the cellular microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of pigment epithelium-derived factor in aged mesenchymal stem cells impairs their therapeutic efficacy for attenuating myocardial infarction injury‡

Liu¹,

Hou²,

Yi³

et al. 2011

European Heart Journal

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AimsMesenchymal stem cells (MSCs) can ameliorate myocardial infarction (MI) injury. However, older-donor MSCs seem less efficacious than those from younger donors, and the contributing underlying mechanisms remain unknown. Here, we determine how age-related expression of pigment epithelium-derived factor (PEDF) affects MSC therapeutic efficacy for MI.Methods and resultsReverse transcriptase–polymerized chain reaction and enzyme-linked immunosorbent assay analyses revealed dramatically increased PEDF expression in MSCs from old mice compared to young mice. Morphological and functional experiments demonstrated significantly impaired old MSC therapeutic efficacy compared with young MSCs in treatment of mice subjected to MI. Immunofluorescent staining demonstrated that administration of old MSCs compared with young MSCs resulted in an infarct region containing fewer endothelial cells, vascular smooth muscle cells, and macrophages, but more fibroblasts. Pigment epithelium-derived factor overexpression in young MSCs impaired the beneficial effects against MI injury, and induced cellular profile changes in the infarct region similar to administration of old MSCs. Knocking down PEDF expression in old MSCs improved MSC therapeutic efficacy, and induced a cellular profile similar to young MSCs administration. Studies in vitro showed that PEDF secreted by MSCs regulated the proliferation and migration of cardiac fibroblasts.ConclusionsThis is the first evidence that paracrine factor PEDF plays critical role in the regulatory effects of MSCs against MI injury. Furthermore, the impaired therapeutic ability of aged MSCs is predominantly caused by increased PEDF secretion. These findings indicate PEDF as a promising novel genetic modification target for improving aged MSC therapeutic efficacy.

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Section: Discussionmentioning

confidence: 99%

Increased expression of pigment epithelium-derived factor in aged mesenchymal stem cells impairs their therapeutic efficacy for attenuating myocardial infarction injury‡

Liu¹,

Hou²,

Yi³

et al. 2011

European Heart Journal

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“…Despite an earlier report showing that the serum concentration of PEDF was decreased in patients with cirrhosis and HCC relative to healthy individuals and to patients with chronic hepatitis 139 , recent results showed that PEDF levels were higher in HCC than in adjacent normal tissues and also greater in serum samples from patients with HCC than normal controls. They also showed that the effective treatment of HCC caused significant reductions in serum PEDF levels 140 . Although this apparent discrepancy may be due to organ- or tissue-specific differences, the overwhelming evidence supports the notion that the lower the tumour PEDF levels, the poorer the prognosis and the worse the expected outcome.…”

Section: Pedf Cancer Prognosis and Therapeutic Potentialmentioning

confidence: 99%

The effects of PEDF on cancer biology: mechanisms of action and therapeutic potential

2013

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The potent actions of pigment epithelium-derived factor (PEDF) on tumour-associated cells, and its extracellular localization and secretion, stimulated research on this multifunctional serpin. Such studies have identified several PEDF receptors and downstream signalling pathways. Known cellular PEDF responses have expanded from the initial discovery that PEDF induces retinoblastoma cell differentiation to its anti-angiogenic, antitumorigenic and antimetastatic properties. Although the diversity of PEDF activities seems to be complex, they are consistent with the varied mechanisms that regulate this multimodal factor. If PEDF is to be used for cancer management, a deeper appreciation of its many functions and mechanisms of action is needed.

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“…PEDF is an endogenous inhibitor of angiogenesis and is neuroprotective. It inhibits the migration of EC in response to proangiogenic factors (10) and induces apoptosis of human EC by activating p38 mitogen-activated protein kinase and caspases (5,22). Increased PEDF expression in the retina results in attenuation of neovascularization through modulation of canonical Wnt signaling (30).…”

mentioning

confidence: 98%

“…PEDF is also expressed in other ocular cell types, including Müller cells, pericytes, and EC (40). PEDF influences the function and pathogenesis of various tissues, including liver, kidney, heart, prostate, and lung, due to its various biological activities (8,12,22,43). PEDF is an endogenous inhibitor of angiogenesis and is neuroprotective.…”

mentioning

confidence: 98%

PEDF expression regulates the proangiogenic and proinflammatory phenotype of the lung endothelium

Shin

Sorenson

2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Pigment epithelium-derived factor (PEDF) is a multifunctional protein with important roles in regulation of inflammation and angiogenesis. It is produced by various cell types, including endothelial cells (EC). However, the cell autonomous impact of PEDF on EC function needs further investigation. Lung EC prepared from PEDF-deficient (PEDF-/-) mice were more migratory and failed to undergo capillary morphogenesis in Matrigel compared with wild type (PEDF+/+) EC. Although no significant differences were observed in the rates of apoptosis in PEDF-/- EC compared with PEDF+/+ cells under basal or stress conditions, PEDF-/- EC proliferated at a slower rate. PEDF-/- EC also expressed increased levels of proinflammatory markers, including vascular endothelial growth factor, inducible nitric oxide synthase, vascular cell adhesion molecule-1, as well as altered cellular junctional organization, and nuclear localization of β-catenin. The PEDF-/- EC were also more adhesive, expressed decreased levels of thrombospondin-2, tenascin-C, and osteopontin, and increased fibronectin. Furthermore, we showed lungs from PEDF-/- mice exhibited increased expression of macrophage marker F4/80, along with increased thickness of the vascular walls, consistent with a proinflammatory phenotype. Together, our data suggest that the PEDF expression makes significant contribution to modulation of the inflammatory and angiogenic phenotype of the lung endothelium.

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Pigment Epithelium-Derived Factor Inhibits Lysosomal Degradation of Bcl-xL and Apoptosis in HepG2 cells

Cited by 20 publications

References 52 publications

Increased expression of pigment epithelium-derived factor in aged mesenchymal stem cells impairs their therapeutic efficacy for attenuating myocardial infarction injury‡

Increased expression of pigment epithelium-derived factor in aged mesenchymal stem cells impairs their therapeutic efficacy for attenuating myocardial infarction injury‡

The effects of PEDF on cancer biology: mechanisms of action and therapeutic potential

PEDF expression regulates the proangiogenic and proinflammatory phenotype of the lung endothelium

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