Collagen VI Enhances Cartilage Tissue Generation by Stimulating Chondrocyte Proliferation

Abstract

Regeneration of human cartilage is inherently inefficient. Current cell-based approaches for cartilage repair, including autologous chondrocytes, are limited by the paucity of cells, associated donor site morbidity, and generation of functionally inferior fibrocartilage rather than articular cartilage. Upon investigating the role of collagen VI (Col VI), a major component of the chondrocyte pericellular matrix (PCM), we observe that soluble Col VI stimulates chondrocyte proliferation. Interestingly, both adult and osteoarthritis chondrocytes respond to soluble Col VI in a similar manner. The proliferative effect is, however, strictly due to the soluble Col VI as no proliferation is observed upon exposure of chondrocytes to immobilized Col VI. Upon short Col VI treatment in 2D monolayer culture, chondrocytes maintain high expression of characteristic chondrocyte markers like Col2a1, agc, and Sox9 whereas the expression of the fibrocartilage marker Collagen I (Col I) and of the hypertrophy marker Collagen X (Col X) is minimal. Additionally, Col VI-expanded chondrocytes show a similar potential to untreated chondrocytes in engineering cartilage in 3D biomimetic hydrogel constructs. Our study has, therefore, identified soluble Col VI as a biologic that can be useful for the expansion and utilization of scarce sources of chondrocytes, potentially for autologous chondrocyte implantation. Additionally, our results underscore the importance of further investigating the changes in chondrocyte PCM with age and disease and the subsequent effects on chondrocyte growth and function.

Centrifugal gravity-induced BMP4 induces chondrogenic differentiation of adipose-derived stem cells via SOX9 upregulation

“…In vitro chondrogenic differentiation may be able to induce fibrotic cartilage or hypertrophic differentiation, which inhibits chondrogenic differentiation [31–33]. Therefore, expression of COL1 (a marker of fibrocartilage) and COL10 (a marker of hypertrophy) was examined in ASCs with or without optimized CG stimulation [34–36]. Protein expression of COL1 was slightly increased by CG stimulation, whereas that of COL10 was dramatically decreased (Fig.…”

Tissue-specific bioactivity of soluble tendon-derived and cartilage-derived extracellular matrices on adult mesenchymal stem cells

“…The inclusion of cartilage ECM structural proteins such as collagen type VI [62], collagen type II, and proteoglycans [63, 64] within MSC-seeded hydrogels has been found to enhance chondrogenic differentiation. Similarly, Almeida et al [28, 65] reported similar improvements when using decellularized cartilage ECM particles.…”

Collagen VI at a glance

“…In a different context, the use of soluble ColVI has been shown to be an important stimulus for the proliferation of both adult and osteoarthritic chondrocytes. This observation suggests that ColVI can be used for the expansion of chondrocytes, such as in autologous chondrocyte transplantation or in tissue-engineering applications (Smeriglio et al, 2015). With regard to bone, Col6a1 −/− mice display abnormalities in the morphology of the knee trabecular bone structure, as revealed by the lower bone volume and connective tissue density, the reduced trabecular number and thickness, and the higher structure model index (a quantitative measure of the trabecular shape) and trabecular separation compared with those of wild-type mice (Christensen et al, 2012).…”