Role of secreted factors regulating canonical and noncanonical WNT signalling in cartilage-bone specification of chondrocytes

• Applicant: Privatdozentin Dr. Solvig Diederichs, since 4/2022
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery ; Cell Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 464119041

Mesenchymal stromal cells (MSC) are an adult multipotent cell population with high potential to differentiate into mesenchymal tissues. However, a tendency of MSC to undergo hypertrophy - the undesirable terminal stage of differentiation during chondrogenesis - limits the clinical application of these cells for cartilage regeneration. Moreover, pathologic induction of the hypertrophy-like changes in chondrocytes is a prominent characteristic of osteoarthritis (OA). Despite numerous efforts, precise regulators of hypertrophic differentiation have not been identified yet. We found that the hypertrophic phenotype of MSC during chondrogenic in vitro differentiation is linked to elevated expression of WNT11 and WNT5A ligands of noncanonical WNT signalling. Additionally, expression levels of other secreted factors known to regulate WNT signalling and to be associated with OA development were found to undergo dramatic changes. However, functional interconnections between these factors and WNT ligands in hypertrophic differentiation have not been established to date. Aim of this study is to elucidate a mechanism for the involvement of identified differentially expressed secreted factors in the regulation of WNT signalling in the context of hypertrophic differentiation of chondrocytes. This would not only impact the cell signalling field of cartilage-bone specification but allow the development of new approaches for manipulation of differentiation outcome of MSC for cartilage neogenesis and regeneration. It also would advance the development of new effective therapeutic protocols that could intervene with the progression of OA in patients.

• DFG Programme: Research Grants
• Co-Investigator: Professor Christof Niehrs, Ph.D.
• Ehemalige Antragstellerinnen: Svitlana Melnik, Ph.D., until 6/2021; Professorin Dr. Wiltrud Richter, from 6/2021 until 3/2022