Microphthalmia-associated transcription factor acts through PEDF to regulate RPE cell migration

Ma, Xiaoyin; Li, Pan; Jin, Xi; Dai, Xiaodan; Li, Huirong; Wen, Bin; Chen, Y.; Ma, Aobo; Qu, Jia; Hou, Ling

doi:10.1016/j.yexcr.2011.11.002

Cited by 23 publications

(18 citation statements)

References 55 publications

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“…It has been reported that PEDF inhibits the migration of breast tumor MDA-MB-231 cells and retinal pigment epithelial (RPE) cells [20, 27]. Thus, the effect of the PEDF-1 and PEDF-2 proteins on cell migration was examined in MDA-MB-231 cells and ARPE-19 cells.…”

Section: Resultsmentioning

confidence: 99%

Identification of Pigment Epithelium-Derived Factor Protein Forms with Distinct Activities on Tumor Cell Lines

Subramanian

Deshpande

Locatelli-Hoops

et al. 2012

Journal of Biomedicine and Biotechnology

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Purpose. Pigment epithelium-derived factor (PEDF) is a multifunctional serpin. The purpose of this study is to identify PEDF protein forms and investigate their biological activities on tumor cell lines. Methods. Recombinant human PEDF proteins were purified by cation- and anion-exchange column chromatography. They were subjected to SDS-PAGE, IEF, deglycosylation, heparin affinity chromatography, and limited proteolysis. Cell viability, real-time electrical impedance of cells, and wound healing assays were performed using bladder and breast cancer cell lines, rat retinal R28, and human ARPE-19 cells. Results. Two PEDF protein peaks were identified after anion-exchange column chromatography: PEDF-1 eluting with lower ionic strength than PEDF-2. PEDF-1 had higher pI value and lower apparent molecular weight than PEDF-2. Both PEDF forms were glycosylated, bound to heparin, and had identical patterns by limited proteolysis. However, PEDF-2 emerged as being highly potent in lowering cell viability in all tumor cell lines tested, and in inhibiting tumor and ARPE-19 cell migration. In contrast, PEDF-1 minimally affected tumor cell viability and cell migration but protected R28 cells against death caused by serum starvation. Conclusion. Two distinct biochemical forms of PEDF varying in overall charge have distinct biological effects on tumor cell viability and migration. The existence of PEDF forms may explain the multifunctional modality of PEDF.

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Section: Resultsmentioning

confidence: 99%

Identification of Pigment Epithelium-Derived Factor Protein Forms with Distinct Activities on Tumor Cell Lines

Subramanian

Deshpande

Locatelli-Hoops

et al. 2012

Journal of Biomedicine and Biotechnology

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“…Retinal pigment epithelial cells form a stable monolayer without migration or proliferation properties in the normal state; however, they can start to migrate and proliferate in disease states. [34][35][36] Microphthalmiaassociated transcription factor and Otx2 have been considered key regulatory transcription factors for RPE specification and differentiation, and they can be upregulated after damage to the RPE layer. [35][36][37] Microphthalmia-associated transcription factor may be involved in promoting melanin pigment synthesis and regulating cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…[34][35][36] Microphthalmiaassociated transcription factor and Otx2 have been considered key regulatory transcription factors for RPE specification and differentiation, and they can be upregulated after damage to the RPE layer. [35][36][37] Microphthalmia-associated transcription factor may be involved in promoting melanin pigment synthesis and regulating cell proliferation. 36,37 Moreover, Otx2 reportedly has a role in maintaining the identity and survival of adult retinal differentiated cells, and elevated expression of Otx2 has been related to reentry of RPE cells into mitosis.…”

Section: Discussionmentioning

confidence: 99%

“…[35][36][37] Microphthalmia-associated transcription factor may be involved in promoting melanin pigment synthesis and regulating cell proliferation. 36,37 Moreover, Otx2 reportedly has a role in maintaining the identity and survival of adult retinal differentiated cells, and elevated expression of Otx2 has been related to reentry of RPE cells into mitosis. 38 In the current study, the time-dependent expression of MiTF and Otx2 was assessed after SRT application.…”

Section: Discussionmentioning

confidence: 99%

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Retinal Pigment Epithelium Responses to Selective Retina Therapy in Mouse Eyes

Kim

Jang

Lee

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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Citation: Kim HD, Jang SY, Lee SH, et al. Retinal pigment epithelium responses to selective retina therapy in mouse eyes. Invest Ophthalmol Vis Sci. 2016;57:3486-3495. DOI:10.1167/iovs.16-19508 PURPOSE. To investigate the characteristics of retinal pigment epithelium (RPE) and retinal damage induced by selective retina therapy (SRT) in mice, and to elucidate longitudinal changes in RPE cells.METHODS. C57BL/6J mice received SRT and continuous-wave laser photocoagulation (cwPC). The cell death pattern was evaluated using TUNEL assay, and proliferative potential of the RPE cells was evaluated using 5-ethynyl-2 0 -dexoyuridine (EdU) assay. To investigate the cell-cell integrity of RPE cells, b-catenin staining was performed. The number and hexagonality of RPE cells in the SRT-treated area were estimated using a Voronoi diagram with time periods of 3 hours to 14 days. Antibodies to microphthalmia-associated transcription factor (MiTF) and orthodenticle homeobox 2 (Otx2) were used to confirm the specific characteristics of RPE cells in the SRT-treated area.RESULTS. The number of TUNEL-positive cells located in the neural retina was significantly lower in lesions treated with SRT compared to those treated with cwPC. EdU-positive RPE cells were first detected 3 to 12 hours after SRT, and increased until 3 to 7 days after SRT. bcatenin staining showed that hexagonality was compromised and subsequently, RPE cells expanded in size within the targeted location. The number of RPE cells in SRT lesions decreased gradually until 12 hours after SRT and recovered by 14 days. Upregulated expression of MiTF and Otx2 was observed for 2 weeks in the SRT lesions.CONCLUSIONS. Selective retina therapy seems to induce selective RPE damage without collateral thermal injury in the neural retina. Furthermore, SRT-treated lesions recovered by proliferation of RPE cells that were present in the treated lesions and by expansion of adjacent RPE cells.Keywords: microphthalmia-associated transcription factor (MiTF), orthodenticle homeobox 2 (Otx2), retinal pigment epithelium, selective retina therapy L aser photocoagulation is a mainstay for the treatment of several retinal conditions associated with retinal pigment epithelium (RPE) dysfunction. 1-4 Continuous-wave laser photocoagulation (cwPC) has been used in the treatment of various macular diseases, such as diabetic macular edema (DME), agerelated macular degeneration, and central serous chorioretinopathy (CSC), over several decades.2-4 Light energy from cwPC is converted into heat in the melanosomes of RPE cells. By heat diffusion, this thermal energy not only damages the RPE but also results in collateral damage of surrounding components, particularly overlying photoreceptors, Bruch's membrane, and choriocapillaries. [5][6][7][8] This is a desired effect because it induces scar formation, which prevents further retinal detachment in retinal holes, and damages photoreceptors during panretinal photocoagulation, which is thought to preserve the central macula in diabetic retinopathy. Howev...

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“…[21][22][23][24][25][26][27] PEDF is a multifaceted NTF that is active in a variety of ocular disorders including diabetic retinopathy and ischemic degeneration. 13,21,28,29 Although major sources of PEDF are choroid, ciliary body, and corneal epithelium, constitutive expression is also detected in RGC and photoreceptors. [30][31][32][33][34][35][36] The upregulation of endogenous PEDF in activated Müller cells and astrocytes may become an RGC neuroprotective source of PEDF during the early stages of degenerative conditions.…”

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confidence: 99%

Pigment Epithelium-Derived Factor Is Retinal Ganglion Cell Neuroprotective and Axogenic After Optic Nerve Crush Injury

Vigneswara¹,

Berry²,

Logan³

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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Citation: Vigneswara V, Berry M, Logan A, Ahmed Z. Pigment epithelium-derived factor is retinal ganglion cell neuroprotective and axogenic after optic nerve crush injury. Invest Ophthalmol Vis Sci. 2013;54: 262454: -263354: . DOI: 10.1167 PURPOSE. To investigate neuroprotective and axogenic properties of pigment epitheliumderived factor (PEDF) in retinal ganglion cells (RGC) in vitro and in vivo.METHODS. Adult rat retinal cultures were treated with combinations of PBS and PEDF with or without a cell permeable analogue of cAMP, and RGC survival and neurite lengths quantified. The optic nerves of anesthetised rats were also crushed intraorbitally to transect all RGC axons followed by intravitreal injections of either PBS, PEDF, or cAMPþPEDF every 7 days. RGC were back filled with FluoroGold to quantify RGC survival and longitudinal optic nerve sections were stained with GAP43 antibodies to detect regenerating RGC axons.RESULTS. An optimal dose of 2.5 3 10 À5 lg/lL, promoted 65% more RGC survival than controls in vitro, increasing by 4.4-and 5-fold the number of RGC with neurites and the mean neurite length, respectively. Addition of cAMP with or without PEDF did not potentiate RGC survival or the mean number of RGC with neurites, but enhanced RGC neurite length by 1.4-fold, compared with PEDF alone. After optic nerve crush (ONC), PEDF protected RGC from apoptosis and increased the numbers of regenerating RGC axons in the optic nerve by 4.6-and 3.4-fold, respectively when compared with controls. cAMP did not enhance PEDF-induced RGC neuroprotection, but potentiated its neuroregenerative effects by 2-to 3-fold, increasing the number of RGC axons regenerating at 500 and 1000 lm from the lesions site.CONCLUSIONS. This study is the first to demonstrate that PEDF enhances both RGC survival and axon regeneration in vitro and in vivo.Keywords: PEDF, retinal ganglion cells, neuroprotection, axon regeneration, optic nerve R etinal ganglion cells (RGC) rapidly die after axotomy, but are protected by combinatorial treatments with neurotrophic factors (NTF), including brain-derived NTF (BDNF), neurotrophin-3/4 (NT-3/4), ciliary neurotrophic factor (CNTF), glial cell line-derived neurotrophic (GDNF), and basic fibroblast growth factor (FGF2). 1-7 NTF combinations also activate intrinsic axon growth signalling pathways that initiate RGC axon regeneration.1-7 Pigment epithelium-derived factor (PEDF) is a 50 kDa NTF glycoprotein belonging to the serpin superfamily, that protects a wide range of central nervous system (CNS) neurons. [8][9][10][11][12][13][14][15] Although first isolated from fetal human retinal pigment (choroid) epithelial cells, like many other NTF, PEDF is expressed in a wide variety of tissues including brain, spinal cord, skeletal muscle, heart, endothelial cells, and osteoblasts. [16][17][18][19][20] PEDF has an array of unique properties including neuroprotective, anti-angiogenic, antiinflammatory, anti-oxidative, and antitumorigenic activities. [21][22][23][24][25][26][27] PEDF is a multifaceted NTF that ...

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Microphthalmia-associated transcription factor acts through PEDF to regulate RPE cell migration

Cited by 23 publications

References 55 publications

Identification of Pigment Epithelium-Derived Factor Protein Forms with Distinct Activities on Tumor Cell Lines

Identification of Pigment Epithelium-Derived Factor Protein Forms with Distinct Activities on Tumor Cell Lines

Retinal Pigment Epithelium Responses to Selective Retina Therapy in Mouse Eyes

Pigment Epithelium-Derived Factor Is Retinal Ganglion Cell Neuroprotective and Axogenic After Optic Nerve Crush Injury

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