The effect of adipose-derived stem cell sheets and CTGF on early flexor tendon healing in a canine model

Hua Shen,Stavros Thomopoulos,Stephen W Linderman,Susumu Yoneda,Younan Xia,Rohith Jayaram,Richard H Gelberman,Shelly E Sakiyama-Elbert

doi:10.1038/s41598-018-29474-8

Abstract

Intrasynovial tendon injuries are among the most challenging in orthopedics. Despite significant improvements in operative and rehabilitation methods, functional outcomes continue to be limited by adhesions, gap formation, and rupture. Adhesions result from excessive inflammation, whereas tendon gapping and rupture result from inflammation-induced matrix degradation and insufficient regeneration. Therefore, this study used a combined treatment approach to modulate inflammation with adipose-derived mesenchymal stromal cells (ASCs) while stimulating tendon regeneration with connective tissue growth factor (CTGF). ASCs were applied to the repair surface via cell sheets and CTGF was delivered to the repair center via porous sutures. The effect of the combined treatment was assessed fourteen days after repair in a canine flexor tendon injury model. CTGF, either alone or with ASCs, reduced inflammatory (IL1B and IL6) and matrix degrading (MMP3 and MMP13) gene expression, while increasing anti-inflammatory gene (IL4) expression and collagen synthesis compared to control repairs. The combined treatment was more effective than CTGF treatment alone, reducing the inflammatory IFNG and scar-associated COL3A1 gene expression and increasing CD146+ tendon stem/progenitor cells at the tendon surface and interior along the core suture tracks. Therefore, the combined approach is promising in promoting early flexor tendon healing and worthy of further investigation.

Highlights

Tendon injuries are common, affecting a large portion of the population and leading to physical impairment and large societal costs[1,2]
In prior studies, we demonstrated that adipose-derived mesenchymal stromal cells (ASCs) modulate tendon responses and facilitate regenerative healing via promotion of macrophage polarization toward the regenerative M2 phenotype and away from the default inflammatory M1 phenotype[10,11]
It was hypothesized that ASCs and connective tissue growth factor (CTGF), by modulating inflammation and promoting matrix synthesis at the repair site, would enhance healing at 14 days after tendon repair

Summary

Introduction

Tendon injuries are common, affecting a large portion of the population and leading to physical impairment and large societal costs[1,2]. In prior studies, we demonstrated that adipose-derived mesenchymal stromal cells (ASCs) modulate tendon responses and facilitate regenerative healing via promotion of macrophage polarization toward the regenerative M2 phenotype and away from the default inflammatory M1 phenotype[10,11]. Growth factors, such as bone morphogenetic protein 12 (BMP 12) and connective tissue growth factor (CTGF), have been shown to stimulate tendon regeneration by inducing exogenous and endogenous stem cell tenogenic differentiation[12,13,14]. These innovative approaches, the current study investigated the effects of concurrent and site-specific applications of ASCs and CTGF on tendon healing using a clinically relevant canine flexor tendon injury and repair model[17,18]. It was hypothesized that ASCs and CTGF, by modulating inflammation and promoting matrix synthesis at the repair site, would enhance healing at 14 days after tendon repair

Methods

Results

Conclusion