Upregulation of matrix metalloproteinase triggers transdifferentiation of retinal pigmented epithelial cells inXenopus laevis: A Link between inflammatory response and regeneration

Abstract

In adult Xenopus eyes, when the whole retina is removed, retinal pigmented epithelial (RPE) cells become activated to be retinal stem cells and regenerate the whole retina. In the present study, using a tissue culture model, it was examined whether upregulation of matrix metalloproteinases (Mmps) triggers retinal regeneration. Soon after retinal removal, Xmmp9 and Xmmp18 were strongly upregulated in the tissues of the RPE and the choroid. In the culture, Mmp expression in the RPE cells corresponded with their migration from the choroid. A potent MMP inhibitor, 1,10-PNTL, suppressed RPE cell migration, proliferation, and formation of an epithelial structure in vitro. The mechanism involved in upregulation of Mmps was further investigated. After retinal removal, inflammatory cytokine genes, IL-1β and TNF-α, were upregulated both in vivo and in vitro. When the inflammation inhibitors dexamethasone or Withaferin A were applied in vitro, RPE cell migration was severely affected, suppressing transdifferentiation. These results demonstrate that Mmps play a pivotal role in retinal regeneration, and suggest that inflammatory cytokines trigger Mmp upregulation, indicating a direct link between the inflammatory reaction and retinal regeneration. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1086-1100, 2017.

Stage-dependent cardiac regeneration inXenopusis regulated by thyroid hormone availability

“…Remarkably, ECM is a privileged TH target. TH significantly regulates a large number of ECM components and remodelling enzymes during Xenopus metamorphosis (22,23,49). Moreover, TH-induced modulations of ECM components and proteases have also been reported in mammalian hearts (50,51).…”

“…5H). Altered expression of matrix metalloproteinases that strongly influence ECM remodelling (22,23,49) may explain the profound change in connective tissue deposition and dynamics observed following cardiac amputation in treated animals (Figs. 4 and 5 and SI Appendix, Fig.…”

“…5H). Moreover, the expression of ECM remodelling enzymes, such as the matrix metalloproteinases mmp2 (also known as gelatinase A), mmp9 (also known as gelatinase B), mmp11 (also known as stromelysin-3), mmp13 (also known as collagenase-3), mmp14 (also known as membrane type 1 matrix metalloproteinase), and fapα ( fibroblast activation protein α), a family of proteinases capable of degrading various components of the ECM and involved in tissue remodelling, also regulated during Xenopus metamorphosis (22,23), was analyzed (Fig. 5H).…”

“…Real-time qPCR reactions were performed in duplicate for each sample using Power SYBR master mix on a QuantStudio 6 Flex Real-Time PCR System (Applied Biosystems), following the manufacturer's recommendations. Primer sequences used for thibz, fn1, col1a1, and tnc are detailed in SI Appendix, Table S1, or already published for mmp2, mmp9, mmp11, mmp13, mmp14, and fapα (22,23). Ct data were collected using ExpressionSuite Software (Applied Biosystems) and analyzed using Excel (Microsoft).…”

Molecular Genetics of Pigment Dispersion Syndrome and Pigmentary Glaucoma: New Insights into Mechanisms

“…Histologic examination has revealed that pigment granules are phagocytosed by both corneal epithelial cells and trabecular meshwork cells rather than being adsorbed onto their surface [ 11 – 14 ]. Phagocytic stress causes alterations to the trabecular meshwork extracellular matrix structure and adhesion [ 15 , 16 ] which could explain the trabecular meshwork dysfunction observed in PDS/PG patients [ 14 ]. In PDS/PG patients, trabecular meshwork cells die and exhibit localized necrosis [ 17 ].…”