Abstract
In vitro chondrogenically differentiated mesenchymal stem cells (MSCs) have a tendency to undergo hypertrophy, mirroring the fate of transient “chondrocytes” in the growth plate. As hypertrophy would result in ossification, this fact limits their use in cartilage tissue engineering applications. During limb development, retinoic acid receptor (RAR) signaling exerts an important influence on cell fate of mesenchymal progenitors. While retinoids foster hypertrophy, suppression of RAR signaling seems to be required for chondrogenic differentiation. Therefore, we hypothesized that treatment of chondrogenically differentiating hMSCs with the RAR inverse agonist, BMS204,493 (further named BMS), would attenuate hypertrophy. We induced hypertrophy in chondrogenic precultured MSC pellets by the addition of bone morphogenetic protein 4. Direct activation of the RAR pathway by application of the physiological RAR agonist retinoic acid (RA) further enhanced the hypertrophic phenotype. However, BMS treatment reduced hypertrophic conversion in hMSCs, shown by decreased cell size, number of hypertrophic cells, and collagen type X deposition in histological analyses. BMS effects were dependent on the time point of application and strongest after early treatment during chondrogenic precultivation. The possibility of modifing hypertrophic cartilage via attenuation of RAR signaling by BMS could be helpful in producing stable engineered tissue for cartilage regeneration.
Highlights
Mesenchymal stem cells (MSCs) are a promising source for the regeneration of articular cartilage defects
After 28 days of cell culture under chondrogenic conditions, aggregates demonstrated a homogenous morphology consisting of small round cells that were surrounded by a uniform ECM very similar to hyaline cartilage structure (Figure 3)
GAGs and collagen type II are typical chondrogenic markers, dimethylmethylene blue (DMMB) staining for GAGs and immunohistochemical staining for collagen type II are strong in hypertrophic MSC aggregates as well
Summary
Mesenchymal stem cells (MSCs) are a promising source for the regeneration of articular cartilage defects They can be obtained from different kinds of tissue (e.g., bone marrow [1] and adipose tissue [2]) and have a high chondrogenic potential [3,4,5,6]. In vivo chondrogenically precultured MSCs showed induction of hypertrophy, vascular invasion, and terminal matrix calcification after ectopic transplantation into mice, whereas implanted human articular chondrocytes kept a stable chondrogenic phenotype without signs of hypertrophy [9]. This indicates discrepancies in the developmental program of chondrogenically differentiated MSCs and articular chondrocytes that have to be overcome to produce appropriate repair tissue
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
