c-Met Modulates RPE Migratory Response to Laser-Induced Retinal Injury
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{"title"=>"C-met modulates rpe migratory response to laser-induced retinal injury", "type"=>"journal", "authors"=>[{"first_name"=>"Masataka", "last_name"=>"Kasaoka", "scopus_author_id"=>"8631644000"}, {"first_name"=>"Jie", "last_name"=>"Ma", "scopus_author_id"=>"55775859200"}, {"first_name"=>"Kameran", "last_name"=>"Lashkari", "scopus_author_id"=>"7003350738"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"84863746874", "pui"=>"365232359", "pmid"=>"22808260", "issn"=>"19326203", "scopus"=>"2-s2.0-84863746874", "doi"=>"10.1371/journal.pone.0040771"}, "id"=>"e28a0c7a-9141-3412-a1db-dfc8ccbb2813", "abstract"=>"Retinal laser injuries are often associated with aberrant migration of the retinal pigment epithelium (RPE), which can cause expansion of the scar beyond the confines of the original laser burn. In this study, we devised a novel method of laser-induced injury to the RPE layer in mouse models and began to dissect the mechanisms associated with pathogenesis and progression of laser-induced RPE injury. We have hypothesized that the proto-oncogene receptor, c-Met, is intimately involved with migration of RPE cells, and may be an early responder to injury. Using transgenic mouse models, we show that constitutive activation of c-Met induces more robust RPE migration into the outer retina of laser-injured eyes, while abrogation of the receptor using a cre-lox method reduces these responses. We also demonstrate that retinal laser injury increases expression of both HGF and c-Met, and activation of c-Met after injury is correlated with RPE cell migration. RPE migration may be responsible for clinically significant anatomic changes observed after laser injury. Abrogation of c-Met activity may be a therapeutic target to minimize retinal damage from aberrant RPE cell migration", "link"=>"http://www.mendeley.com/research/cmet-modulates-rpe-migratory-response-laserinduced-retinal-injury", "reader_count"=>9, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>3, "Researcher"=>1, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>1, "Student > Master"=>2, "Lecturer > Senior Lecturer"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>3, "Researcher"=>1, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>1, "Student > Master"=>2, "Lecturer > Senior Lecturer"=>1}, "reader_count_by_subject_area"=>{"Agricultural and Biological Sciences"=>4, "Medicine and Dentistry"=>5}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>5}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>4}}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/610395"], "description"=>"<p>After sham laser injury, very trace c-Met expression was detected in the control retina (A). c-Met expression was increased up to day 3 (B). On day 7 and 14, c-Met expression (C – D) decreased but remained higher than control (A). Similarly, in TPR-Met mice, c-Met expression significantly increased after laser injury (F) although obvious expression was found in sham-treated eyes (control; E). c-Met expression decreased from day 7 to day 14. On day 7, migrated c-Met positive cells were observed in the outer retina (C – D, G – H). On day 14, the disrupted RPE layer was reformed as a monolayer (D, H). Expression of (phosphorylated) p-Met was similar between B6 and TPR-Met mice (I – P). p-Met was not detected in control retina of B6 mice (I), but p-Met was detected as early as 3–6 hr after the laser injury. Expression of p-Met in the laser-treated areas obviously diminished (J) on day 3 and was almost undetected from day 7 to day 14 (K – L). Several p-met positive migrating cells were observed after day 7 (K – L). p-Met expression was found in the control retina of TPR-Met mice (M) and dramatically increased on day 1 after the laser injury (N – P). Some migrated cells were detected from day 7 to day 14 (O – P). Expression of p-Met in TPR-Met mice after laser treatment was higher than in B6 mice (I – P). Expression of RPE65 in B6 mice on day 7 after laser treatment was significantly higher than other conditions (S) but there was no difference between control, day 3 and day 14 (Q – R, T). In TPR-Met mice, RPE65 expression slightly decreased after laser injury on day 1 compared to control (U – V), but significantly increased from day 7 to day 14 (W – X). The RPE layer in B6 and TPR-Met mice showed disorganized morphology after laser burns up to day 3 but started to reform on day 7 and completely reformed on day 14. The expression of c-Met in B6 and TPR-Met mice rapidly increased after the laser injury (SS1). However, p-Met did not show obvious changes after the laser burns (SS2). Expression of RPE65 in laser-treated B6 and TPR-Met mice was quite similar between B6 and TPR-Met mice at different time point (SS3). The scale bar for all images: 100 µm. * P<0.05, independent samples <i>t</i>-test.</p>", "links"=>[], "tags"=>["changes", "p-met", "rpe65", "retina", "b6", "tpr-met", "mice"], "article_id"=>280881, "categories"=>["Neuroscience", "Cell Biology", "Developmental Biology", "Medicine"], "users"=>["Masataka Kasaoka", "Jie Ma", "Kameran Lashkari"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0040771.g005", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Dynamic_changes_in_expression_of_c_Met_p_Met_and_RPE65_in_the_retina_of_B6_and_TPR_Met_mice_after_laser_injury_/280881", "title"=>"Dynamic changes in expression of c-Met, p-Met and RPE65 in the retina of B6 and TPR-Met mice after laser injury.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 02:36:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/610743"], "description"=>"<p>RPE cells were observed to migrate into ONL and expressed both c-Met and p-Met (A – E); RPE65 expression confirmed that migrating cells were indeed RPE (C and F). RPE migration was observed as early as 3 days after injury. More robust RPE migration was observed in TPR-Met mice (left side in G panel). In AAV-Cre injected mice, significantly fewer migrating cells were found compared with their AAV-GFP injected counterparts (right side in G panel, * P<0.05, independent samples <i>t</i>-test). These observations indicate that higher c-Met expression could induce more RPE cells to migrate. Significant linear association was confirmed between c-Met expression and duration of laser injury, specifically from day 3 to day 14 in both B6 mice (y = −0.50× +0.11, R<sup>2</sup> = 0.82) and TPR-Met mice (y = −0.16× +0.13, R<sup>2</sup> = 0.52) (H). On day 14 after the laser injury, expression of c-Met in both mice gradually decreased back to baseline (control level, open circles on the right side). But the process in B6 mice may be faster (slope value, -0.50) than in TPR-Met mice (slope value, -0.16). In addition, a significant linear regression was found between the concentration of c-Met and the number of migrated RPE cells in the c-Met over-expressed TPR-Met mice (y = 0.83× +1.02, R<sup>2</sup> = 0.62) (inserted graph in H panel, the values on x-axis and y-axis were log<sub>10</sub>-transformed according to the original measurements). These findings strongly suggest that higher levels of c-Met expression could induce more RPE cells to migrate. The scale bar for all images: 100 µm.</p>", "links"=>[], "tags"=>["rpe", "cells", "retina", "days", "b6"], "article_id"=>281232, "categories"=>["Neuroscience", "Cell Biology", "Developmental Biology", "Medicine"], "users"=>["Masataka Kasaoka", "Jie Ma", "Kameran Lashkari"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0040771.g007", "stats"=>{"downloads"=>4, "page_views"=>73, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Migration_of_RPE_cells_into_outer_retina_7_days_after_to_injury_in_B6_mice_/281232", "title"=>"Migration of RPE cells into outer retina 7 days after to injury in B6 mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 02:38:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/610900"], "description"=>"<p>The primers for detecting the mRNA change after the laser treatment in the retinas of C57BL/6 mice.</p>", "links"=>[], "tags"=>["primers", "detecting", "mrna", "retinas"], "article_id"=>281387, "categories"=>["Neuroscience", "Cell Biology", "Developmental Biology", "Medicine"], "users"=>["Masataka Kasaoka", "Jie Ma", "Kameran Lashkari"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0040771.t002", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_primers_for_detecting_the_mRNA_change_after_the_laser_treatment_in_the_retinas_of_C57BL_6_mice_/281387", "title"=>"The primers for detecting the mRNA change after the laser treatment in the retinas of C57BL/6 mice.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-20 02:38:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/609735"], "description"=>"<p>TUNEL is a common method for detecting DNA fragmentation that results from apoptotic signaling cascades. No significant morphological disorganization was observed in the retina within hours after laser burns (A, D). Nuclei in ONL exhibited signs of apoptosis about 12 hr after laser injury (B – C) and reached the apoptosis peak by day 3 (E – F, TUNEL-positive nuclei labeling with green fluorescence). The apoptotic and dead cells were indicated by red and white arrowheads, respectively (G – I). Scale bar for images: 100 µm. Abbreviations (the same in the following Figures): B6 mice, C57BL/6 mice; INL, inner nuclear layer; ONL, outer nuclear layer; RPE, retinal pigment epithelium.</p>", "links"=>[], "tags"=>["deoxynucleotidyl", "transferase", "dutp", "nick", "labeling", "indicated", "induced", "apoptosis", "b6"], "article_id"=>280220, "categories"=>["Neuroscience", "Cell Biology", "Developmental Biology", "Medicine"], "users"=>["Masataka Kasaoka", "Jie Ma", "Kameran Lashkari"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0040771.g002", "stats"=>{"downloads"=>9, "page_views"=>22, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Terminal_deoxynucleotidyl_transferase_dUTP_nick_end_labeling_TUNEL_indicated_that_laser_injury_induced_early_apoptosis_in_the_outer_nuclear_layer_ONL_in_B6_mice_/280220", "title"=>"Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) indicated that laser injury induced early apoptosis in the outer nuclear layer (ONL) in B6 mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 02:32:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/610593"], "description"=>"<p>Mice were scarified on day 14 after laser application (total day, 28). In AAV-GFP injected mice, laser burns induced an expected increase in c-Met and p-Met (B vs. A; E vs. F). There was no detectable c-Met or p-Met expression was seen after subretinal AAV-Cre injection (C and G). Less c-Met and no p-Met expressed were observed even after laser injury (D and H). RPE65 expression was not affected by subretinal injection of AAV-GFP or AAV-Cre injection (I – L). There were more migrated RPE cells in ONL in AAV-Cre injected (L) compared to AAV-GFP injected mice (J). There was very limited c-Met and p-Met detected in AAV-Cre injected eyes before and after laser injury (SS1– SS2); in AAV-GFP injected eyes, c-Met expression expectedly increased after laser treatment (SS1) (* P<0.05, independent samples <i>t</i>-test). RPE65 expression was not affected by either AAV-GFP or AAV-Cre injection (SS3).</p>", "links"=>[], "tags"=>["p-met", "rpe65", "mice", "14", "days", "aav-gfp", "aav-cre", "burns"], "article_id"=>281081, "categories"=>["Neuroscience", "Cell Biology", "Developmental Biology", "Medicine"], "users"=>["Masataka Kasaoka", "Jie Ma", "Kameran Lashkari"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0040771.g006", "stats"=>{"downloads"=>1, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_c_Met_p_Met_and_RPE65_expression_in_c_Met_fl_fl_mice_14_days_after_AAV_GFP_and_AAV_Cre_injections_respectively_A_C_E_G_I_and_K_without_laser_burns_and_after_laser_burns_B_D_F_H_J_and_L_/281081", "title"=>"c-Met, p-Met and RPE65 expression in c-Met<sup>fl/fl</sup> mice 14 days after AAV-GFP and AAV-Cre injections, respectively (A, C, E, G, I and K) without laser burns; and after laser burns (B, D, F, H, J and L).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 02:37:10"}
  • {"files"=>["https://ndownloader.figshare.com/files/610038"], "description"=>"<p>Tissue were embedded in paraffin and stained with hematoxylin and eosin. Eye receiving sham laser injury shows intact retina and RPE layers (A). At 12–24 hr after the laser burns, INL and ONL begin to show structural disorganization with some photoreceptors loss (B – C). RPE monolayer was disrupted and pigmented cells were observed in the subretinal space (red arrow; C). On day 3, significant photoreceptors loss was observed in conjunction within the laser-injured area (D). No photoreceptor was found in the injury area at day 14 (E, indicated by blue arrows). The RPE monolayer reformed at the wounded area suggesting reformation of a new blood-retina barrier (F, indicated by red arrows). The scale bar for all images: 100 µm. Abbreviation: GCL, ganglion cell layer.</p>", "links"=>[], "tags"=>["images", "morphological", "retinal", "b6"], "article_id"=>280531, "categories"=>["Neuroscience", "Cell Biology", "Developmental Biology", "Medicine"], "users"=>["Masataka Kasaoka", "Jie Ma", "Kameran Lashkari"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0040771.g003", "stats"=>{"downloads"=>3, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Representative_images_of_morphological_features_in_the_retinal_layer_following_laser_burn_injury_in_B6_mice_/280531", "title"=>"Representative images of morphological features in the retinal layer following laser burn injury in B6 mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 02:34:01"}
  • {"files"=>["https://ndownloader.figshare.com/files/609464"], "description"=>"<p>(C) Before AAV-Cre injection, retina lysates of c-Met<sup>fl/fl</sup> mice were prepared for genotyping by PCR reaction. A 380 bp amplification fragment was specific to the floxed allele (a and c); a 300 bp fragment to the wild-type allele (e); in AAV-Cre injected mice, a 650 bp fragment was detected specific to the deleted allele (b, indicated by a red arrowhead) while mice subretinally injected with AAV-GFP did not show the corresponding band (d).</p>", "links"=>[], "tags"=>["diagram", "tpr-met", "mice", "schematic", "cre-mediated", "knock-out", "c-met", "aav-cre", "delivered", "subretinally", "homozygous"], "article_id"=>279940, "categories"=>["Neuroscience", "Cell Biology", "Developmental Biology", "Medicine"], "users"=>["Masataka Kasaoka", "Jie Ma", "Kameran Lashkari"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0040771.g001", "stats"=>{"downloads"=>2, "page_views"=>30, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Structural_diagram_of_cMet_in_TPR_Met_mice_A_and_schematic_of_Cre_mediated_knock_out_of_c_Met_by_AAV_Cre_delivered_subretinally_in_the_homozygous_c_Met_fl_fl_mice_B_/279940", "title"=>"Structural diagram of <i>cMet</i> in TPR-Met mice (A) and schematic of Cre-mediated knock-out of c-Met by AAV-Cre delivered subretinally in the homozygous c-Met<sup>fl/fl</sup> mice (B).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 02:30:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/610824"], "description"=>"<p>We presume the accumulation of HGF expression might be able to trigger the expression of c-Met. Meanwhile, the c-Met expression positively affected the RPE cell migration after the laser injury.</p>", "links"=>[], "tags"=>["hgf", "c-met", "rpe", "cells", "b6", "laser-induced"], "article_id"=>281313, "categories"=>["Neuroscience", "Cell Biology", "Developmental Biology", "Medicine"], "users"=>["Masataka Kasaoka", "Jie Ma", "Kameran Lashkari"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0040771.g008", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_expression_of_HGF_and_c_Met_and_the_migration_of_RPE_cells_in_B6_mouse_after_the_laser_induced_injury_/281313", "title"=>"The expression of HGF and c-Met and the migration of RPE cells in B6 mouse after the laser-induced injury.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 02:38:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/610261"], "description"=>"<p>Data are presented as fold increase over sham-treated eyes and normalized to expression of GAPDH. mRNA expression of c-Met, the cognate receptor for HGF, reached its peak value around 12 hr after the laser injury (A), while mRNA level of HGF peaked at 3 hr (B) (indicated by arrows in C, respectively). A hysteresis relationship was identified between the expression of c-Met and HGF (arrowheads, C). (D) Expression of phosphorylated c-Met (p-Met) did not show any significant change over time after laser application. Abbreviations: HGF, hepatocyte growth factor; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; Con, control retinas received sham laser burns; IHC, immunohistochemical staining. *P<0.05 (Mann–Whitney U test, n = 5).</p>", "links"=>[], "tags"=>["laser-injured", "retinas", "b6"], "article_id"=>280754, "categories"=>["Neuroscience", "Cell Biology", "Developmental Biology", "Medicine"], "users"=>["Masataka Kasaoka", "Jie Ma", "Kameran Lashkari"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0040771.g004", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Quantified_gene_expression_in_laser_injured_retinas_of_B6_mice_/280754", "title"=>"Quantified gene expression in laser-injured retinas of B6 mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 02:35:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/610868"], "description"=>"<p>Summary of mice used in this study (verified by genotyping).</p>", "links"=>[], "tags"=>["mice"], "article_id"=>281369, "categories"=>["Neuroscience", "Cell Biology", "Developmental Biology", "Medicine"], "users"=>["Masataka Kasaoka", "Jie Ma", "Kameran Lashkari"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0040771.t001", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Summary_of_mice_used_in_this_study_verified_by_genotyping_/281369", "title"=>"Summary of mice used in this study (verified by genotyping).", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-20 02:38:49"}

PMC Usage Stats | Further Information

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Relative Metric

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