Evaluating regeneration of composite tissue injury models in MRL/MpJ and C57Bl/6 mice: a comparative study

Abstract

Scarring after composite tissue injuries of the hands, such as avulsion injuries, is a grave clinical condition. Currently, the scope for improvement of healing outcomes of these wounds through surgical intervention is inadequate, and may precede a need for amputation if tissue loss is extensive. The study of models of mammalian regenerative healing may provide insights into how similar composite tissue regeneration could be stimulated in humans. One such example is the MRL/MpJ mouse, which displays regenerative healing of some tissues, including the ear pinna, cornea and patellar tendon. Notably, not all tissue types regenerate in MRL/MpJ mice, indicating a degree of tissue specificity to this phenomenon. The basis of the variable healing phenotype across different tissues is still unknown. The project described herein aimed to characterise the healing phenotype of a novel model of digit composite tissue injury in MRL/MpJ mice, in comparison with C57Bl/6 control mice. This healing profile was compared with that of the regenerative composite tissue punch injury of the ear pinna, by immunohistochemical and proteomic analyses. Additionally, three novel models of ex vivo corneal injury were developed, to examine epithelial wounding isolated from systemic factors. The findings of these analyses were used to inform a pilot manipulation study of MRL/MpJ ear healing. Ex vivo corneal assays indicated that, in an isolated system, corneal epithelial healing is similar between mouse strains. However, the in vivo studies highlighted differences in patterns of ear and digit tissue synthesis following its removal, both between mouse strains, and between injury models. These differences were associated with variations in patterns of macrophage infiltration, cell proliferation, angiogenesis, myofibroblast activity and collagen synthesis. Proteomic analysis further suggested cellular processes which may be driving the phenotypic differences observed between mouse strains, and between injury models. Manipulation of one of these highlighted pathways in vivo in MRL/MpJ mice showed preliminary evidence of the inhibition of both ear and digit healing. This project indicated potential mechanistic bases for the MRL/MpJ regenerative ear healing phenotype, and established the novel model of digit injury as a promising subject of future study.

Date of Award	31 Dec 2022
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Simon Webb (Supervisor), Jason Wong (Supervisor), David Ansell (Supervisor), Enrique Amaya (Supervisor) & Andrew Weightman (Supervisor)