Chondrogenic differentiation of mesenchymal stem cells: challenges and unfulfilled expectations

Abstract

Articular cartilage repair and regeneration provides a substantial challenge in Regenerative Medicine because of the high degree of morphological and mechanical complexity intrinsic to hyaline cartilage due, in part, to its extracellular matrix. Cartilage remains one of the most difficult tissues to heal; even state-of-the-art regenerative medicine technology cannot yet provide authentic cartilage resurfacing. Mesenchymal stem cells (MSCs) were once believed to be the panacea for cartilage repair and regeneration, but despite years of research, they have not fulfilled these expectations. It has been observed that MSCs have an intrinsic differentiation program reminiscent of endochondral bone formation, which they follow after exposure to specific reagents as a part of current differentiation protocols. Efforts have been made to avoid the resulting hypertrophic fate of MSCs; however, so far, none of these has recreated a fully functional articular hyaline cartilage without chondrocytes exhibiting a hypertrophic phenotype. We reviewed the current literature in an attempt to understand why MSCs have failed to regenerate articular cartilage. The challenges that must be overcome before MSC-based tissue engineering can become a front-line technology for successful articular cartilage regeneration are highlighted.

FIG. 1.

Cartilage development. Oversimplified scheme of cartilage development highlighting the generation of different types of cartilages derived from the cranial neural crest (craniofacial cartilage), paraxial mesoderm (axial cartilage), and lateral plate mesoderm (appendicular cartilage). Cartilage diversification may not be entirely dependent on tissue development; it seems probable that environmental factors are involved in cartilage determination. For example, hyaline cartilage can be derived from three different developmental lineage paths, whereas its functional specification is determined by its specific anatomic location. Thus, we suggest that these hyaline cartilages are influenced by site-specific and different physiological and physical or mechanical signals. Color images available online at www.liebertpub.com/teb

FIG. 2.

Chondrogenic lineage progression of mesenchymal stem cells (MSCs). MSCs appear to be limited to follow an endochondral ossification program, which will end in vascular penetration, marrow deposition, and ossification of this cartilaginous tissue. Differentiation toward the stable hyaline cartilage phenotypes is theoretically restricted. However, it is possible that reproducing the complex environmental signals that are required for pathway switching has not been discovered. Bypassing these restrictions may be possible using reprogramming technology (induced pluripotent stem [iPS]) or embryonic stem cells (ESCs) as a new start state. Dashed arrows indicate possible routes, although evidence is lacking about the detailed differentiation pathway. Figure made with images available at Servier Medical Art (www.servier.fr). Color images available online at www.liebertpub.com/teb