Development and maintenance of tendons and ligaments

Abstract

Tendons and ligaments are fibrous connective tissues vital to the transmission of force and stabilization of the musculoskeletal system. Arising in precise regions of the embryo, tendons and ligaments share many properties and little is known about the molecular differences that differentiate them. Recent studies have revealed heterogeneity and plasticity within tendon and ligament cells, raising questions regarding the developmental mechanisms regulating tendon and ligament identity. Here, we discuss recent findings that contribute to our understanding of the mechanisms that establish and maintain tendon progenitors and their differentiated progeny in the head, trunk and limb. We also review the extent to which these findings are specific to certain anatomical regions and model organisms, and indicate which findings similarly apply to ligaments. Finally, we address current research regarding the cellular lineages that contribute to tendon and ligament repair, and to what extent their regulation is conserved within tendon and ligament development.

Keywords: Enthesis; Fgf; Fibrous connective tissue; Ligament; Scx; Tendon; Tenocyte.

Fig. 1.

Tissue morphology of tendon, ligament, and musculoskeletal junctions of the human elbow. (Clockwise from top right) Tendons (which connect muscle to bone) and ligaments (which connect and stabilize bones) share similar properties but have slightly different orientation of collagen fibrils; whereas tendons have parallel arrangements of fibrils, ligament fibrils can overlap and cross. The tendon enthesis features graded, intermediate tissue types that facilitate the transmission of force from tendon to bone, whereas the myotendinous junction facilitates the joining of tendon and muscle through interactions of ECM proteins.

Fig. 2.

Embryonic origins and molecular regional regulators of tendon and ligament progenitors in the developing mouse. Tendons and ligaments are derived from mesenchyme of multiple embryonic origins with cranial tendons and ligaments originating from cranial neural crest cells (CNCCs; blue), limb tendons and ligaments from lateral plate mesoderm (yellow), axial tendons from paraxial mesoderm (pink), and neck and shoulder tendons and ligaments from a mixture of all three (green). In addition to their multiple origins, tendon and ligament progenitors require regional mechanisms for their establishment.

Fig. 3.

Tendon progenitor induction, differentiation, maintenance and maturation in the mouse limb. Induction of Scx in tendon progenitors relies on Tgfβ signaling during embryonic development. Later, tendon cells differentiate and multiply in the presence of mechanical stimulation from the muscle, as well as undetermined secreted factors from surrounding tissue, including cartilage. Various inputs are required for both the establishment and maintenance of the tendon cell fate. E, embryonic day; P, postnatal day.

Fig. 4.

Regulation of cell fate during development of the tendon-bone attachment in the mouse limb. The enthesis is derived from attachment progenitors (APs), which have the potential to form endochondral bone, fibrocartilage and tendon. (A) Tgfβ is necessary to establish APs, which co-express Scx and Sox9. Once established, APs give rise to either Scx⁺ tenocytes, which make tendon, or Sox9⁺ chondrocytes, which make fibrocartilage and bone. Some APs may maintain co-expression of Scx and Sox9, and acquire a hybrid tenochondral phenotype. (B) The APs form as a secondary condensation atop the primary cartilage anlagen at the site of tendon insertion at E12.5. (C) By E13.5, the graded nature of the enthesis begins to emerge; however, it is not known if the intermediate tissue forming at the tendon-bone interface is made from hybrid tenochondral cell type (cells that co-express Scx and Sox9) and/or from discrete cell types (tenocytes and chondrocytes) that intermingle and/or are separated by a cellular boundary. (D) By E14.5-15.5, the graded enthesis has formed, connecting tendon to bone. E, embryonic day.

Fig. 5.

Cellular lineages contributing to tendon and enthesis repair in mice. Injuries to the tendon and enthesis heal through the formation of a persistent fibrovascular scar that does not recapitulate the native morphology or mechanical properties of the original tissue. Cells contributing to tendon repair originate from the tendon proper (green cell) and the tendon sheath (orange cell), whereas cells contributing to enthesis healing can be sourced from either tendon or bone (beige cell). A few cell-specific markers that characterize putative tendon stem/progenitor cells (TSPCs) or enthesis stem/progenitor cells (ESPCs) have been identified. Asterisks indicate markers found in tendon sheath-derived cells.