Regenerative properties of fetal sheep tendon are not adversely affected by transplantation into an adult environment

Abstract

Tendon injuries account for a significant number of musculoskeletal afflictions each year. While new surgical techniques and rehabilitation protocols have led to improved clinical outcomes, postsurgical scarring remains the most problematic aspect of tendon repair. In contrast to this typical pattern of fibrosis, recent studies have shown that fetal tendon is capable of healing without scar. However, whether this regenerative healing pattern is intrinsic to the fetal tissue itself or the result of its environment is not known. Thus, the objective of this study is to examine the influence of an adult environment on healing in adult and fetal tendons. We hypothesized that injured fetal tendon tissue transplanted into an adult environment would retain a regenerative healing pattern after injury, demonstrating normal histological and mechanical properties. Our results support this hypothesis. Histological analyses revealed considerable alterations in adult tendon transplants after injury while fetal transplants showed no abnormalities. The injured adult tendons also demonstrated elevated levels of TGF-b1, bFGF, and CD44 at the wound site, whereas the fetal specimens showed little or no such changes in response to injury. The data from our biomechanical studies further corroborate these observations, with significant decreases in the stiffness, modulus, and almost all viscoelastic properties in wounded versus unwounded adult tendons, and fetal specimens showing no differences in mechanical properties between the wounded and unwounded groups. Thus, the results of our investigation demonstrate that the adult environment is not an impediment to scarless repair and that this capability is intrinsic to the fetal tendon itself. Our study also begins to provide insight into the mechanisms controlling this regenerative response. ß

Fetal ACL Fibroblasts Exhibit Enhanced Cellular Properties Compared with Adults

“…The average migration rate for adult ACL fibroblasts that we measured was lower than that reported for MCL fibroblasts. Furthermore, fetal ACL fibroblasts migrated at a rate comparable to fetal tenocytes isolated from lateral extensor tendons of sheep (35.76 ± 6.08 lm/hour) [9], which heal regeneratively [7,17]. Our findings also parallel those of a recent investigation comparing the motility and contractile ability of fetal and adult dermal fibroblasts [49].…”

“…It is possible the healing response of the ACL may not be inherently poor, but age-dependent. Scarless healing in fetal tissues, such as skin and tendon, has been attributed to the intrinsic properties of fetal cells [17,35]. Cell migration and extracellular matrix production are believed important cellular responses facilitating tissue repair.…”

“…Characterization of the fetal environment has revealed a shift toward an anti-inflammatory cytokine expression profile with a concomitant reduction in the number of localized inflammatory cells [1,27,31,32]. Furthermore, fetal cells themselves promote scarless healing even outside their native environment [17,35]. Understanding the fetal environment and the cellular characteristics of fetal cells may lead to the discovery of specific factors (ie, soluble signaling molecules) that could be used in the clinical setting to improve wound repair.…”

Periostin Secreted by Mesenchymal Stem Cells Supports Tendon Formation in an Ectopic Mouse Model

“…This causes significant dysfunction and disability leading to re-injury in the long term. Specifically, adult tendons lack a true regeneration capacity that, however, is present in the fetus [2]. Therefore, identification of those specific properties contributing to regeneration during ontogenesis but not previously implicated in tendon formation will be informative and may help to devise biological strategies for tendon regeneration.…”

Sirt-1 Is Required for the Inhibition of Apoptosis and Inflammatory Responses in Human Tenocytes

“…They play an important role in producing extracellular matrix and in initiating regenerative responses following injury or degeneration. The poor vascularization of tendon seems to be a major reason for its limited healing capacity (1). Overuse tendon injury and tendinopathies are a growing problem in sports medicine and orthopedic practice that affects a large proportion of the aging Western population (2, 3).…”