Authors Chasan, S. ; Hesse, E. ; Atallah, P. ; Gerstner, M. ; Diederichs, S. ; Schenker, A. ; Grobe, K. ; Werner, C. ; Richter, W.
Title Glycosaminoglycan sulfation as niche instruction feature to direct chondral versus endochondral in vivo differentiation of mesenchymal stroma cells
Date 20.04.2022
Number 60261
Abstract Articular cartilage has a low regeneration capacity and frequently fails to repair after injury, posing a severe risk for development of osteoarthritis (OA). OA is an age-associated disease and, in view of an expanding aging population, there is an increasing demand for regenerative therapies to meet this clinical need. Harnessing human mesenchymal stroma cells (MSC) for articular cartilage regeneration is still hampered by an inability to steer cells into the chondral developmental pathway to obtain articular chondrocytes (AC) with a stable phenotype. Pre-differentiated MSC have not entered any clinical trials for cartilage repair yet, since virtually all chondrogenic protocols induce overactivation of pro-hypertrophic pathways resulting in endochondral differentiation, chondrocyte hypertrophy, tissue mineralization and bone formation in vivo. Lineage commitment of skeletal stem cells depends on microenvironmental cues from the stem-cell niche and we postulated that mimicking the natural niche by presentation of developmentally important glycosaminoglycans like heparan sulfate (HS) will allow to guide tissue morphogenesis into the chondral developmental pathway in vivo. Rationale was to suppress over-activation of the pro-hypertrophic growth factor pathways hedgehog (HH)-, BMP- and WNT-signaling by the presence of HS or related molecules which are known to activate or sequester various growth factors depending on sulfation levels. Aim of the study was to display different HS-patterns on a biomaterial seeded with MSC to direct skeletal stem cell fate between alternate lineages in vivo, the chondral and the endochondral pathway. Specific goal was to grow mineralization-resistant neocartilage from MSC by rational design of a heparin-activated hydrogel allowing i) efficient retention of the master inducer TGFß as most important driver of chondrogenesis ii) sustained and concerted suppression of pro-hypertrophic HH, BMP and WNT-signaling dependent on sulfation levels and iii) provision of the benefits of an injectable in situ forming hydrogel to avoid laborious, and cost-intensive in vitro pre-differentiation culture.
Publisher Osteoarthritis and Cartilage
Citation Osteoarthritis and Cartilage 30 (2022) S58-S59

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