Regulation of Tissue Regeneration in Zebrafish by Vitamin D Signaling

Abstract

Adult mammals have limited regenerative capacities. Lost limbs are replaced by scar tissues. Heart attacks lead to massive cardiomyocyte death without robust proliferative response at the injury sites, resulting in permanently impaired cardiac function. While current treatments mainly rely on drug, tissue transplantation, cell therapy and tissue engineering, there remains an urgent need for new strategies to promote regeneration due to limitations in efficiency and specificity in existing approaches. Previous research in our lab identified vitamin D as a potent pro-regenerative factor in zebrafish. To further determine the role of vitamin D signaling in regeneration, we applied drug treatments, generated transgenic zebrafish, and performed proliferation and regeneration essays to examine the necessity and sufficiency of the pathway in regulating fin and heart regeneration. In addition, we designed a novel system to allow spatial and temporal sensitization of tissue’s response to vitamin D signaling utilizing the tissue regeneration enhancer elements (TREEs) and tested this for its ability to promote regeneration in a tissue-specific way. Key findings from this study are: 1) vitamin D signaling is required for zebrafish fin and heart regeneration; 2) enhanced vitamin D signaling promotes fin and heart regeneration; 3) Temporal overexpression of vitamin D receptor at injury sites regulated by TREEs enables locally sensitized response to vitamin D signaling and improves fin regeneration without global effects in zebrafish.