In a joint keynote lecture Claudia Angeli (University of Lousiville and Kentucky Spinal Cord Injury Research Center, Frazier Rehab Institute) and Dustin Shillcox described one of the extraordinary successes recently achieved by regenerative medicine. Shillcox was paralysed from the chest down at age 26 years after a car accident. Classified as ‘sensory and motor complete’ after being injured at T5, he was told he had no chance of recovering movement. But hope that he might move his arms and legs again came from research led by Angeli in collaboration with Reggie Edgerton (UCLA) and Susan Harkema (University of Louisville). Angeli’s work focuses on mechanisms by which human locomotion is controlled following neurologic injury. She has found that the use of epidural stimulation and activity-based retraining of the nervous system following spinal cord injury increases the excitability of spinal cord neurons and augments return of function.1,2 Shillcox participated in Angeli’s research as a subject and today has regained the extraordinary ability to voluntarily control his legs and toes over brief time periods.

A long-standing question in regeneration biology is why mammals, including humans, possess a relatively poor regenerative ability, while some other vertebrates and many invertebrate animals have an extraordinary capacity to regenerate even highly complex tissues. Epimorphic regeneration, by which a proliferating blastema gives rise to new tissue, is the default regeneration mode for appendage injury in non-amniotic vertebrates, such as salamanders, frog tadpoles and zebrafish. In contrast, this process is extremely rare in mammals and instead tissue injury typically stimulates scar formation. Unlike most mammals, rabbits have been known for decades to be exceptional in regenerating ear wounds by blastema formation. Research led by Ashley Seifert (University of Kentucky) has discovered a similar ability in another mammal, the African spiny mouse (Acomys).3 Ear puncture wounds in Acomys exhibit all the hallmarks of a blastema, such as formation and maintenance of an active wound epidermis, cell cycle re-entry and cell proliferation, delayed revascularisation, and formation of a proregenerative extracellular matrix. Besides ear regeneration, this species has a propensity for skin tearing under very low tension due to a porous extracellular matrix rich in collagen type III. Although similar conditions exist in humans and are associated with disease, Acomys utilise this strategy to escape predators by shedding off their skin. Remarkably, upon skin loss (including dermis) rapid wound contraction is followed by hair follicle regeneration in dorsal skin wounds and scar-free healing. Understanding the precise mechanisms by which this vertebrate species repairs large skin wounds and completely regenerates ear puncture holes may inform development of therapies for promoting more effective wound healing and regeneration in humans.

The ultimate key in understanding tissue healing is to monitor this process in living animals. A molecule of great interest for its important functions in a variety of wound-repair processes is hydrogen peroxide (H 2 O 2 ), which has been implicated in leukocyte migration and axon repair. Far less is known about its role in re-epithelialisation during which epidermal keratinocytes migrate over the injured area to re-establish a protective skin barrier. Research led by Sandra Rieger (MDI Biological Laboratory) utilised in vivo imaging of larval zebrafish to explore the dynamics of H 2 O 2 during keratinocyte migration. Comparative studies with human keratinocytes uncovered a conserved role for low but not high levels of H 2 O 2 in oxidative regulation of Inhibitor of kappa B kinase alpha (Ikkα). In differentiated keratinocytes Ikkα represses EGFR activity,4,5 whereas oxidation leads to EGFR de-repression. Thus, Ikkα appears to be a redox sensor within epidermal keratinocytes to control the switch between a differentiated and migratory (EGF-dependent) cell fate after injury (S Rieger, unpublished).

The classical wound repair model describes proliferation and migration as essential steps to promote wound closure. Could alternative mechanisms have a role and if so how are they regulated? Vicki Losick (postdoctoral associate of Allan Spradling, Carnegie Institution for Science; now at MDI Biological Laboratory) asked this question. By utilising the adult fruit fly as a model for studying epidermal wound repair, her work uncovered a previously unknown repair mechanism by which cells grow to become polyploid instead of dividing, also known as wound-induced polyploidy. In this process, upon injury cells at the wound edge enlarge in size and form a very large multinucleated syncytium, which facilitates resealing of the epidermis.6 Further investigations showed that wound-induced polyploidy is regulated by the Hippo signalling pathway to fine tune the extent of polyploidy, possibly with respect to wound size. Polyploid cells are often observed in mammalian tissues in response to injury, stress, and/or aging, and thus wound-induced polyploidy appears to be an evolutionarily conserved mechanism to compensate for cell loss.