Comparison of Tendon Development Versus Tendon Healing and Regeneration

Abstract

Tendon is a vital connective tissue in human skeletal muscle system, and tendon injury is very common and intractable in clinic. Tendon development and repair are two closely related but still not fully understood processes. Tendon development involves multiple germ layer, as well as the regulation of diversity transcription factors (Scx et al.), proteins (Tnmd et al.) and signaling pathways (TGFβ et al.). The nature process of tendon repair is roughly divided in three stages, which are dominated by various cells and cell factors. This review will describe the whole process of tendon development and compare it with the process of tendon repair, focusing on the understanding and recent advances in the regulation of tendon development and repair. The study and comparison of tendon development and repair process can thus provide references and guidelines for treatment of tendon injuries.

Keywords: comparison; development; healing; regeneration; regulation; tendon.

FIGURE 1

Tendons at different locations have different embryonic origins. Tendons at the cranial region are originated from the neural crest. Some of the nerve crest cells from the ectoderm migrate to the cranial area and differentiate into tendon progenitors. The axial tendons are derived in the syndetome, a dorsolateral stripe of the sclerotome at the junction between adjacent myotomes. At a cross section of embryo, the LPM is formed on either side of the central axis and is subdivided into anterior and posterior parts, corresponding to four limb buds. In limb buds, tendon progenitors are derived from the mesenchyme directly under the ectoderm, in locations that follow the proximal-to-distal outgrowth of the limb bud.

FIGURE 2

Expression of tendon markers in tenocytes during tendon development. (A) Mesenchymal cells differentiate into Scx-expressing tendon progenitor cells, which also partially express Sox9. Scx⁺Sox9⁺ progenitor cells differentiate into the tenocytes which are located near the bone in the enthesis. Other progenitor cells gradually express normal tendon markers during maturation. The classic enthesis is composed of four layers. From tendon to bone end are tendon layer, fibrocartilage layer, mineralized fibrocartilage layer and bone layer respectively. The mature tendon is composed by collagen fascicles which are assembled collagen fibrils, with some tenocytes attached around. (B) In mouse limbs, Scx expression begin to increase at E9.5 and continue to increase until tenocyte maturation. Slight Mkx expression is detectable in tendon at E12.5, after the emergence of Scx and robust Mkx mRNA expression at E13.5 and E14.5, stages at which the tendon progenitors undergo condensation and differentiation. Egr1 transcripts are first expressed at E12.5 in Scx domains forming tendon, and they are expressed in long tendons at E16.5. Egr2 is first detectable in E14.5 limb tendons and is generally expressed in all limb tendons by E16.5. Tnmd is highly expressed in E14.5 and is considered a late tendon marker.

FIGURE 3

Regulation of tendon development in embryogenesis. Scleraxis (Scx) is the first signaling molecule implicated in tendon progenitor cell initiation, whereas Mohawk (Mkx) and early growth response 1 and 2 (Egr1, Erg2) are secondary signals for tendon differentiation and maturation. Thrombospondins (Thbs) and tenomodulin (Tnmd) are upstream factors which regulate collagen and matrix. FGF, TGFβ and Wnt signaling pathways regulate the induction of Scx. GDF5,6,7,8, mTORC1 and Wnta3 regulate the upstream transcription factors. Mechanical stimulation is involved in regulation via the TGFβ and FGF signaling pathway. Notably, the effects of FGF on chicken embryo and mouse embryo appear to be opposite. Mesenchymal progenitors are maintained by ectodermal Wnts and repressed by mesenchymal Wnts.

FIGURE 4

The tendon repair process. The response to adult tendon injury is composed of three blurred-defined stages. The first stage, defined as inflammatory stage, spans a couple of days typically. The injured area is infiltrated with erythrocyte, leukocytes, and platelets secreting key growth factors and endothelial chemoattractants. During the next stage, macrophages synthesize and release growth factors, and induce cells to recruit towards injury region, and change their role from phagocytosis to reparation with a couple of days. In the meantime, tenocytes secrete a serious of matrixes consist mainly of collagen III. At this time, bFGF and VEGF expressed from recruited cells like tenocytes, fibroblasts and inflammatory cells reaches a peak, thus promoting cellular proliferation and angiogenesis. In the final stage, main activity that happens is a process of remodeling. A great amount of collagen I begins to be synthesized, and the ECMs deposited among the injured area become more organized. However, the cell density and synthetic activity in repaired region are not able to recover to normal conditions. This stage appears roughly one or two months after the injury and persistent for more than 1 year.