The search for the holy stromal cell - Identification and characterization of specialized and regenerative stromal cell populations to accelerate cartilage repair
Knee osteoarthritis (KOA) is one of the most common form of joint disease among elderly patients and remains a major orthopedic challenge since mature hyaline articular cartilage has only a limited capacity for intrinsic repair. Despite its prevalence, the molecular mechanisms triggering KOA are poorly characterized and there are currently no disease modifying therapies that can halt or revert KOA. Cell therapeutic approaches using autologous chondrocytes or mesenchymal stromal cells (MSCs) have been developed and tested in the last decade. MSCs can be found in bone marrow, adipose-tissue, synovium and cartilage itself, and are capable of differentiating into osteogenic, chondrogenic and adipogenic lineages. First attempts to inject MSCs in KOA patients have provided promising results during clinical trials, showing a significant decrease in inflammation and enhanced joint function. However, in most studies, regeneration of cartilage was not observed. Our preliminary results and current literature suggest that the MSCs inhibiting inflammation and the MSCs regenerating cartilage are not one and the same.
The overall aim of this project is to delineate the MSC subpopulations in the synovial membrane and the epiphyseal bone marrow area, to conceptualize a novel mixed MSC population therapeutic strategy for KOA. The project has both a wet-lab and dry-lab outcomes. The wet-lab outcomes will entail delineating MSC subpopulations using novel scRNA-seq techniques and perform functional assays to characterize the cells for their differentiation, regeneration, and immunomodulatory capacity. In the dry-lab, mathematical models will be derived from the data to explain the macro-level dynamics; attractants and surrounding factors that are required for maintenance and re-activation of chondrogenic MSCs during ageing.
1. Weber, M.-C.*, Fischer, L.*, Damerau, A., Ponomarev, I., Pfeiffenberger, M., Gaber, T., Götschel, S., Lang, J., Röblitz, S., Buttgereit, F., Ehrig, R. & A. Lang (2020) Macroscale mesenchymal condensation to study cytokinedriven cellular and matrix-related changes during cartilage degradation. Biofabrication (in press) https://doi.org/10.1088/1758-5090/aba08f.
2. Addo, R.K., Heinrich, F., Heinz, G.A., Schulz, S., Sercan‐Alp, Ö., Lehmann, K., Tran, C.L., Bardua, M., Matz, M., Löhning, M., Hauser, A.E., Kruglov, A., Chang, H.-D., Durek, P., Radbruch, A., Mashreghi, M.F. (2019) Single‐cell transcriptomes of murine bone marrow stromal cells reveal niche‐associated heterogeneity. European Journal of Immunolology, 49: 1372-1379.