A critical role for thrombin in vertebrate lens regeneration

Abstract

Lens regeneration in urodele amphibians such as the newt proceeds from the dorsal margin of the iris where pigment epithelial cells (PEC) re-enter the cell cycle and transdifferentiate into lens. A general problem in regeneration research is to understand how the events of tissue injury or removal are coupled to the activation of plasticity in residual differentiated cells or stem cells. Thrombin, a pivotal regulator of the injury response, has been implicated as a regulator of cell cycle re-entry in newt myotubes, and also in newt iris PEC. After removal of the lens, thrombin was activated on the dorsal margin for 5-7 days. Inactivation of thrombin by either of two different inhibitors essentially blocked S-phase re-entry by PEC at this location. The axolotl, a related species which can regenerate its limb but not its lens, can activate thrombin after amputation but not after lens removal. These data support the hypothesis that thrombin is a critical signal linking injury to regeneration, and offer a new perspective on the evolutionary and phylogenetic questions about regeneration.

Beyond early development: Xenopus as an emerging model for the study of regenerative mechanisms

“…It might be expected that the early triggers which promote regenerative responses over simple wound healing would be conserved regardless of the system studied, be it limb, tail or lens, whereas later tissue specific patterning events would be different depending on the system analyzed. This seems to be the case in some urodele amphibians, where the clotting protease thrombin is linked to the de-differentiation process in regeneration of tail and limb, but is not involved in development (Tanaka et al, 1999;Imokawa et al, 2004) This system, however, does not seem to play the same role in Xenopus, perhaps explaining the more limited regenerative power of anurans. In an attempt to identify the shared genes, Wolfe et al (2004) used differential screening to identify genes that were preferentially expressed in both hindlimb regeneration (st. 51-53, 1-3 days after amputation) and cornea to lens trandifferentiation.…”

Global analysis of gene expression inXenopushindlimbs during stage‐dependent complete and incomplete regeneration

“…Conflicting data from FGL2-deficient mice experiments show that FGL2 may or may not contribute to immunologically mediated thrombosis (Marsden et al, 2003;Hancock et al, 2004). Thrombin, proposed to be activated by tissue factor (TF) appears to couple injury and regeneration (lens and limb) in urodele amphibians (Imokawa et al, 2004). Because FGL2 bypasses the TF/ factor VII extrinsic thrombin activation pathway (Marsden et al, 2003), we speculate that FGL2 may lead to thrombin activation in anuran amphibians by a TF-independent pathway.…”

Shared Triggering Mechanisms of Retinal Regeneration in Lower Vertebrates and Retinal Rescue in Higher Ones

“…In our experiments on Urodela when eye surgery was applied for retinal removal the occlusion of choroidal small vessels, an inflammation, and a decrease of a tension of the eye back wall tissues represented the very first events that brought later to RPE cell-type conversion, cell proliferation, and withdrawal from the layer (Grigoryan & Mitashov, 1979). Recently it was shown that in newts the thrombin (a participant of hemostasis and other immediate responses to any damage) pretends to be a regulator of iris cell transdifferentiation (Imokawa & Brockes, 2003;Imokawa et al, 2004). It is known that thrombin derives from prothrombin when activated by coagulation factors and, in particular, by transmembrane protein TF (tissue factor).…”