The alchemy of tendon repair: a primer for the (S)mad scientist

Abstract

During vertebrate development, mesenchymal progenitors capable of forming bone, cartilage, muscle, fat, or tendon arise from either neural crest or somitic mesoderm. Transcriptional programs that specify mesenchymal cell fates are initiated and modified by paracrine cues provided by TGF-beta superfamily members and mediated in part via the regulated assembly of Smad-containing multiprotein transcription factor complexes. In this issue of the JCI, Hoffmann and colleagues have identified that Smad8 activation drives tendon formation from C3H10T1/2 cells, a murine cell line that recapitulates many features of normal multipotent mesenchymal cells (see the related article beginning on page 940). Cells programmed to the tenocyte cell fate in vitro formed tenogenic grafts in vivo. These results add to the accumulating evidence that proliferating, multipotent mesenchymal progenitor cells can be programmed to yield multiple cell types--e.g., osteoblasts, myocytes, chondrocytes, and tenocytes--that may be useful in cell-based therapeutic approaches to musculoskeletal diseases.

Figure 1. Organizational structure of tendon.

Tendon is a nonmineralized, dense regular connective tissue that consists primarily of type I collagen. The major executive cell type of tendon, the tenocyte, synthesizes and secretes trihelical tropocollagen that is assembled and cross-linked in parallel fibrillar arrays. Higher-order organization of these arrays is provided by the endotenon, a loose connective tissue layer that envelopes collagen fibrils to form tendon fascicles. Fascicles in turn are bundled together by the epitenon, a layer contiguous with the endotenon through which the microvasculature traverses and provides nutrient supply (1, 2). Dependent upon anatomic venue, the tendon either may (e.g., hand flexor tendon) or may not (e.g., Achilles tendon) be housed within a synovial sheath (1, 2).

Figure 2. Lineage programming of mesenchymal progenitors: a working model.

(A) During development, mesenchymal progenitors capable of forming bone, cartilage, muscle, fat, or tendon arise from either neural crest or from mesoderm. Transcriptional programs (shown in italics) that specify mesenchymal cell fates are initiated and modified by paracrine cues provided by TGF-β superfamily members, mediated via regulated assembly of Smad-containing multiprotein transcription factor complexes (8). During somitic mesoderm lamination, the syndetome — demarcated by Scleraxis expression — forms at the interface between the bone-forming sclerotome and muscle-forming myotome to generate tenocytes of axial tendons (3). Similar mechanisms are likely deployed during appendicular tendon formation. Not shown are the influences of paracrine Wnt and FGF signaling cascades and homeodomain proteins of the Pax, Msx, Dlx, and Six families that modulate BMP signaling. The data reported by Hoffmann et al. (5) indicate that activated Smad8 promotes tenocyte differentiation of C3H10T1/2 cells. Whether Smad8 participates in syndetome development is unknown. C/EBP, CCAAT/enhancer binding protein; MRF, muscle regulatory factor; MRTF, myocardin-related transcription factor; SRF, serum response factor. (B) R-Smad and L+MH2 structures. Although the MH1 domain encodes a DNA-binding function, Smad interaction with other transcription factors is required for gene regulation; these interactions are directed by the L+MH2 domain (8). The SxS motif is the cognate for phosphorylation-dependent Smad activation by activin-like kinase receptors. Smad4 and importins mediate nuclear entry. Since the Smad8 L+MH2 fragment lacks intrinsic DNA binding, its tenogenic actions are mediated by regulatory protein-protein interactions.