Bevacizumab modulates epithelial‐to‐mesenchymal transition in the retinal pigment epithelial cells via connective tissue growth factor up‐regulation

Chen, Ching‐Long; Liang, Chang-Min; Chen, Yi-Hao; Tai, Ming‐Cheng; Lu, Da‐Wen; Chen, Jiann‐Torng

doi:10.1111/j.1755-3768.2012.02426.x

Cited by 22 publications

(22 citation statements)

References 47 publications

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“…This recovered 2 weeks later. Furthermore, cell culture studies suggested anti-VEGF agents cause RPE dedifferentiation (14), reduced barrier function (15), permeability (16), and impaired phagocytosis (17), but have no effect on apoptosis (18). Therefore, complete VEGF inhibition may be detrimental, but given the variability in reported effects, modifying factors could influence patient response and risk of developing side effects.…”

Section: Introductionmentioning

confidence: 99%

VEGF regulates local inhibitory complement proteins in the eye and kidney

Keir¹,

Firth²,

Aponik³

et al. 2016

Journal of Clinical Investigation

125

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Outer retinal and renal glomerular functions rely on specialized vasculature maintained by VEGF that is produced by neighboring epithelial cells, the retinal pigment epithelium (RPE) and podocytes, respectively. Dysregulation of RPE- and podocyte-derived VEGF is associated with neovascularization in wet age-related macular degeneration (ARMD), choriocapillaris degeneration, and glomerular thrombotic microangiopathy (TMA). Since complement activation and genetic variants in inhibitory complement factor H (CFH) are also features of both ARMD and TMA, we hypothesized that VEGF and CFH interact. Here, we demonstrated that VEGF inhibition decreases local CFH and other complement regulators in the eye and kidney through reduced VEGFR2/PKC-α/CREB signaling. Patient podocytes and RPE cells carrying disease-associated CFH genetic variants had more alternative complement pathway deposits than controls. These deposits were increased by VEGF antagonism, a common wet ARMD treatment, suggesting that VEGF inhibition could reduce cellular complement regulatory capacity. VEGF antagonism also increased markers of endothelial cell activation, which was partially reduced by genetic complement inhibition. Together, these results suggest that VEGF protects the retinal and glomerular microvasculature, not only through VEGFR2-mediated vasculotrophism, but also through modulation of local complement proteins that could protect against complement-mediated damage. Though further study is warranted, these findings could be relevant for patients receiving VEGF antagonists.

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Section: Introductionmentioning

confidence: 99%

VEGF regulates local inhibitory complement proteins in the eye and kidney

Keir¹,

Firth²,

Aponik³

et al. 2016

Journal of Clinical Investigation

125

View full text Add to dashboard Cite

show abstract

“…In contrast, CXCL12 rescued photoreceptors in a model of retinal injury . Uniquely, CTGF was shown to regulate RPE transdifferentiation and cooperate with growth factor signaling for tissue protection in vivo .…”

Section: Resultsmentioning

confidence: 96%

Multimodal Delivery of Isogenic Mesenchymal Stem Cells Yields Synergistic Protection from Retinal Degeneration and Vision Loss

Bakondi

Girman

Lü

et al. 2016

Stem Cells Translational Medicine

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We previously demonstrated that subretinal injection (SRI) of isogenic mesenchymal stem cells (MSCs) reduced the severity of retinal degeneration in Royal College of Surgeons rats in a focal manner. In contrast, intravenous MSC infusion (MSCIV) produced panoptic retinal rescue. By combining these treatments, we now show that MSCIV supplementation potentiates the MSCSRI‐mediated rescue of photoreceptors and visual function. Electrophysiological recording from superior colliculi revealed 3.9‐fold lower luminance threshold responses (LTRs) and 22% larger functional rescue area from combined treatment compared with MSCSRI alone. MSCIV supplementation of sham (saline) injection also improved LTRs 3.4‐fold and enlarged rescue areas by 27% compared with saline alone. We confirmed the involvement of MSC chemotaxis for vision rescue by modulating C‐X‐C chemokine receptor 4 activity before MSCIV but without increased retinal homing. Rather, circulating platelets and lymphocytes were reduced 3 and 7 days after MSCIV, respectively. We demonstrated MSCSRI‐mediated paracrine support of vision rescue by SRI of concentrated MSC‐conditioned medium and assessed function by electroretinography and optokinetic response. MSC‐secreted peptides increased retinal pigment epithelium (RPE) metabolic activity and clearance of photoreceptor outer segments ex vivo, which was partially abrogated by antibody blockade of trophic factors in concentrated MSC‐conditioned medium, or their cognate receptors on RPE. These data support multimodal mechanisms for MSC‐mediated retinal protection that differ by administration route and synergize when combined. Thus, using MSCIV as adjuvant therapy might improve cell therapies for retinal dystrophy and warrants further translational evaluation. Stem Cells Translational Medicine 2017;6:444–457

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“…Chen et al 41 showed that treatment with bevacizumab induced an epithelial-to-mesenchymal transition in the lineage of human retinal pigment epithelium cells (ARPE 19) by upregulation of the connective tissue growth factor, a profibrotic factor associated with the process of fibrosis. 42 Using the same cell line, Schnichels et al 43 also observed a slightly enhanced effect on cell death after bevacizumab treatment.…”

Section: Discussionmentioning

confidence: 99%