Evolutionary adaptations in developmental signaling pathways underlie regenerative scar-free wound repair in African Spiny Mouse (Genus Acomys)

Thesis (Ph.D.)--University of Washington, 2018Vertebrate tissue regeneration is a property restricted to a small number of species within the teleost and urodele clades. Contrary to these assumptions, however, all mammalian species examined are also capable of regeneration in utero. However, this ability is lost at birth and repair is redirected to inflammation and scar tissue formation. This response, if left unchecked, will lead to organ failure. Evolutionary adaptations to avoid predation in the form of autotomy or self-amputation have allowed adult Acomys cahirinus (Egyptian Spiny Mouse) to escape this developmental transition to scar formation and instead repair external skin injuries in a scar free regenerative manner with complete restoration of hair follicles, cartilage, vasculature and peripheral neurons. Intriguingly, A. cahirinus have not dispensed altogether with injury activation of the myofibroblast (MF), the cellular contributor to scar tissue formation. Rather, A. cahirinus has evolved non-canonical MF functions that do not drive fibrosis. In identifying unique molecular signatures associated with this phenotype, RNA seq analysis identifies key regulatory modifications of the Hippo-YAP pathway, a critical pathway in embryonic development. Specifically, the pathway effector protein YAP (Yes Associated protein) is reactivated in a biphasic manner, which is necessary for mediating in vivo regenerative repair. These phases include blastema formation, late stage reorganization and restoration of tissue architecture. The dynamic YAP activity observed is in part mediated by a PP2A-mediated surveillance phosphatase that rapidly and specifically dephosphorylates YAP regulatory residues. In addition to external skin repair, further investigation reveals A. cahirinus homeostatic adaptations to resist scar tissue formation are also found to extend to the kidney. Utilizing models of renal fibrosis that induce progressive kidney failure in muriod rodents, A.cahirinus restore kidney function with no apparent fibrotic scar tissue. Elucidating the genomic changes evolution has produced in A.cahirinus promises to provide new therapeutic approaches to treat fibropathologies currently affecting millions of individuals worldwide