Cell non-autonomous functions of S100a4 drive fibrotic tendon healing.

Jessica E Ackerman,Emma Knapp,Valentina Studentsova,Alayna E Loiselle,Anne Ec Nichols,Katherine T Best

doi:10.7554/elife.45342

Abstract

Identification of pro-regenerative approaches to improve tendon healing is critically important as the fibrotic healing response impairs physical function. In the present study we tested the hypothesis that S100a4 haploinsufficiency or inhibition of S100a4 signaling improves tendon function following acute injury and surgical repair in a murine model. We demonstrate that S100a4 drives fibrotic tendon healing primarily through a cell non-autonomous process, with S100a4 haploinsufficiency promoting regenerative tendon healing. Moreover, inhibition of S100a4 signaling via antagonism of its putative receptor, RAGE, also decreases scar formation. Mechanistically, S100a4 haploinsufficiency decreases myofibroblast and macrophage content at the site of injury, with both cell populations being key drivers of fibrotic progression. Moreover, S100a4-lineage cells become α-SMA+ myofibroblasts, via loss of S100a4 expression. Using a combination of genetic mouse models, small molecule inhibitors and in vitro studies we have defined S100a4 as a novel, promising therapeutic candidate to improve tendon function after acute injury.

Highlights

Tendons are composed primarily of a dense, highly aligned collagen extracellular matrix (ECM), and connect muscle to bone to transmit mechanical forces throughout the body
S100a4Lin+ cells were located in the native tendon and bridging scar tissue at D7 and D14 post-surgery (Figure 1B)
Consistent with the role of S100a4 as a key driver of fibrosis (Bruneval et al, 2005; Iwano et al, 2002; Lawson et al, 2005; Tomcik et al, 2015), we have demonstrated that S100a4 promotes scar-mediated tendon healing primarily via cell-non-autonomous extracellular signaling

Summary

Introduction

Tendons are composed primarily of a dense, highly aligned collagen extracellular matrix (ECM), and connect muscle to bone to transmit mechanical forces throughout the body. Scar tissue increases tendon bulk and forms adhesions to the surrounding tissues, impeding normal range of motion (ROM) This pathological response to injury represents a major clinical burden considering there are over 300,000 surgical tendon repairs in the United States annually (Pennisi, 2002), and a high proportion of primary tendon repairs heal with unsatisfactory outcomes and impaired function (Aydin et al, 2004; Galatz et al, 2004). We have identified S100a4 haploinsufficiency as a novel model of regenerative tendon healing and defined a requirement for S100a4+ cells in the restoration of mechanical properties during tendon healing These data identify S100a4 signaling as a novel target to improve tendon healing and demonstrate the efficacy of pharmacological inhibition of S100a4 signaling to improve functional outcomes during healing

Results

Discussion

Materials and methods

Ethics statement