Abstract
BackgroundHuman TGF-β3 has been used in many studies to induce genes coding for typical cartilage matrix components and accelerate chondrogenic differentiation, making it the standard constituent in most cultivation media used for the assessment of chondrogenesis associated with various stem cell types on carrier matrices. However, in vivo data suggests that TGF-β3 and its other isoforms also induce endochondral and intramembranous osteogenesis in non-primate species to other mammals. Based on previously demonstrated improved articular cartilage induction by a using hTGF-β3 and hBMP-6 together on hADSC cultures and the interaction of TGF- β with matrix in vivo, the present study investigates the interaction of a chitosan scaffold as polyanionic polysaccharide with both growth factors. The study analyzes the difference between chondrogenic differentiation that leads to stable hyaline cartilage and the endochondral ossification route that ends in hypertrophy by extending the usual panel of investigated gene expression and stringent employment of quantitative PCR.ResultsBy assessing the viability, proliferation, matrix formation and gene expression patterns it is shown that hTGF-β3 + hBMP-6 promotes improved hyaline articular cartilage formation in a chitosan scaffold in which ACAN with Col2A1 and not Col1A1 nor Col10A1 where highly expressed both at a transcriptional and translational level. Inversely, hTGF-β3 alone tended towards endochondral bone formation showing according protein and gene expression patterns.ConclusionThese findings demonstrate that clinical therapies should consider using hTGF-β3 + hBMP-6 in articular cartilage regeneration therapies as the synergistic interaction of these morphogens seems to ensure and maintain proper hyaline articular cartilage matrix formation counteracting degeneration to fibrous tissue or ossification. These effects are produced by interaction of the growth factors with the polysaccharide matrix.
Highlights
Human TGF-β3 has been used in many studies to induce genes coding for typical cartilage matrix components and accelerate chondrogenic differentiation, making it the standard constituent in most cultivation media used for the assessment of chondrogenesis associated with various stem cell types on carrier matrices
Building on previous results for the interaction of transforming growth factor β (TGF-β) with chitosan, we aim to investigate whether combinations with other TGF-β superfamily members, human bone morphogenetic protein 6 (hBMP-6), increases articular cartilage formation potential as compared to the effect of TGF-β3 used alone or in combination with IGF-I
Mechanical properties could not be measured directly, as compression forces were below the range of our equipment, but they can be considered similar as described in other publications, as reviewed e.g. by Levengood et al 2014 [49]
Summary
Human TGF-β3 has been used in many studies to induce genes coding for typical cartilage matrix components and accelerate chondrogenic differentiation, making it the standard constituent in most cultivation media used for the assessment of chondrogenesis associated with various stem cell types on carrier matrices. Healthy articular cartilage lacks self-repairing capacities due to its avascular structure This makes selfregeneration and self-healing impossible, unlike bone, which can lead to functional limitations and pain eventually associated to osteoarthritis [1,2,3,4]. Stem cell-based therapies are an alternative to overcome the poor self-repair capacity of cartilage, where, under the principle of tissue engineering, an insoluble substratum is combined with soluble signals [13,14,15]. Chondrocytes or stem cells are often combined with a biomimetic biomaterial that supports the formation of neo-cartilage tissue with the typical characteristics of hyaline articular cartilage [16]
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