Mechanisms underlying adult tendon regeneration in the zebrafish

Galloway, Jenna L Project Summary Model organisms such as the zebrafish have advanced our mechanistic understanding of regeneration, with the hope that this knowledge could eventually impact the design of treatments for human injury and disease. Due to their important function in transferring load from the muscle to the bone, tendons are often injured and yet, have limited healing potential in humans. Work in the mouse has provided a cellular and molecular understanding of mammalian tendon healing. However, in the mouse, as in all mammals, adult tendons do not regenerate. Instead, injuries heal via scar formation, resulting in disorganized tissue with inferior properties. This application proposes to use the zebrafish, a highly tractable genetic and regenerative model organism, to study adult tendon regeneration. We have shown that TGFβ signaling is required for adult zebrafish tendon regeneration and the contribution of scleraxis (scxa)-lineage cells to the healing tissue. We also find decreased scxa:mcherry+ cells at the injury site upon reduced muscle activity via Botox-injection to the neighboring muscle. As TGFβ signaling is thought to be downstream of muscle activity in tendon development and homeostasis, we propose to examine the relationship between TGFβ signaling and muscle activity in tendon regeneration. First, we will investigate how reduced TGFβ signaling and muscle activity affect the cellular composition and fate of the cells involved in regeneration. Using an inducible genetic system, we will test the temporal and spatial regulation of TGFβ signaling in scxa-cell recruitment and tendon regeneration. Finally, we will test if diminished muscle activity alters TGFβ signaling and if activation of TGFβ signaling can rescue the disruption to scxa-cell recruitment and tendon regeneration. Using a transcriptomics approach, we also aim to discover new pathways that are differentially regulated in regenerative compared with non-regenerative contexts and test their function in regeneration. Together, these aims will provide new mechanistic insight into the role of TGFβ signaling and muscle activity in tendon homeostasis and regeneration and hopes to impact future tendon treatment strategies in humans.