What we should know before using tissue engineering techniques to repair injured tendons: a developmental biology perspective

Abstract

Tendons connect muscles to bones, and serve as the transmitters of force that allow all the movements of the body. Tenocytes are the basic cellular units of tendons, and produce the collagens that form the hierarchical fiber system of the tendon. Tendon injuries are common, and difficult to repair, particularly in the case of the insertion of tendon into bone. Successful attempts at cell-based repair therapies will require an understanding of the normal development of tendon tissues, including their differentiated regions such as the fibrous mid-section and fibrocartilaginous insertion site. Many genes are known to be involved in the formation of tendon. However, their functional roles in tendon development have not been fully characterized. Tissue engineers have attempted to generate functional tendon tissue in vitro. However, a lack of knowledge of normal tendon development has hampered these efforts. Here we review studies focusing on the developmental mechanisms of tendon development, and discuss the potential applications of a molecular understanding of tendon development to the treatment of tendon injuries.

FIG. 1.

The hierarchical architecture of tendon. Collagen proteins form a triple helix structure and self-assemble with other collagen molecules to establish the characteristic tendon matrix. Bundles of fibrils form tendon fascicles, the larger primary fiber bundles. Groups of fascicles are bound together by a thin layer of connective tissue named endotenon. Several fiber bundles and endotenon are encompassed by the epitenon. The epitenon is covered by another layer of connective tissue named paratenon. The paratenon and eiptenon are called peritenon.

FIG. 2.

The current model of tendon differentiation in trunk (A) and limb (B). (A) FGF8 from the myotome activates expression of SCX via PEA3 and ERM to induce the subjacent sclerotome cells to become tendons. The sclerotomal factors PAX1 and SOX5/6 inhibit the expression of SCX and allow the sclerotome to develop into cartilage. (B) The initiation of SCX expression in the limb is still unknown. TGFβ signaling promotes maintenance and recruitment of tendon progenitors and is essential for tendon formation, whereas the homeobox transcription factor Mohawk (MKX) is required for the maturation of tendon. BMP signals have negative influence on tendon development. The roles of other mesenchymal factors on tendon differentiation remain to be characterized. Not, notochord; NT, neural tube; FGF, fibroblast growth factor; SCX, scleraxis; TGFβ, transforming growth factor β; BMP, bone morphogenetic protein.