Abstract 480: Mammalian Organ Regeneration In Spiny Mice

Abstract

Fibrosis-driven solid organ failure is a major global health burden. Spiny mice (genus: Acomys ) are terrestrial mammals that regenerate severe skin wounds without scars to avoid predation. To test whether spiny mice can also regenerate internal organ injuries, we performed acute obstructive or ischemic surgeries on adult kidneys of Acomys cahirinus compared to Mus musculus. Despite equivalent acute tissue damage, Acomys fully regenerate nephron structure, vascular & lymphatic networks, and organ function without fibrosis by 14d while Mus (CD1 or C57BL/6) develop extensive interstitial fibrosis and progress to organ failure and death. Comparative transcriptomic, epigenetic, and single-cell assays revealed that the Acomys genome appears poised to initiate a regenerative response at the time of injury. In addition, we found the Hippo pathway effector protein YAP localized to the nucleus in renal tubular epithelial cells (RTEs) undergoing scarless wound healing in Acomys while it was either cytoplasmic or not detectable in Mus RTEs. Experiments in vitro revealed an accelerated PP2A-dependent YAP phosphatase activity that maintained nuclear YAP in Acomys RTEs and was not detected in Mus or human cells. Treatment of Acomys in vivo with the nuclear YAP-TEAD inhibitor verteporfin converted tissue regeneration to fibrosis in the dermis and similar experiments for the kidney are in progress. These results suggest that the spiny mouse genome evolved both transcriptional and post-translational adaptations important for scar-free regenerative wound healing in vivo .