Analysis of clonal dynamics, development and potential of mesenchymal stem cells

• Applicant: Dr. Michael Rothe
• Subject Area: Hematology, Oncology ; Cell Biology
• Term: since 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 326520460

Mesenchymal stromal cells (MSCs) are used in clinical trials to treat various diseases. The ability of MSCs to inhibit an excessive immune reaction is of key therapeutic interest. In the current COVID-19 pandemic, MSCs were successfully used to treat severe cases of the disease. However, to date, there are no harmonized cell culture conditions or efficacy assays for MSCs, so clinical outcomes can be highly variable. In the initial application phase, we demonstrated that MSCs are a heterogeneous population with many initial clones of different functionality. During the expansion phase, individual clones were selected over time. This selection process was dependent on the cell culture medium. We used specific fluorescent labels and DNA barcodes to follow the clonal evolution of MSC cultures. We were also able to study the influence of several cytokines on the growth and function of MSCs. MSCs can be activated by proinflammatory cytokines to enhance their immunoinhibitory effects. We plan to investigate this, among other things, at the single cell level in the proposed follow-up project. We also plan to modify the umbilical cord tissue, from which MSCs are derived, with viral vectors. This would allow us to equip MSCs with new and enhanced immunomodulatory capabilities. Modified tissue pieces could thus generate new therapeutic cell material of consistent quality for months. Although MSC-mediated immunomodulation plays a central role for therapeutic use in humans, there are other promising approaches for using the cells. In the previous project, we were able to use conditioned medium from TGFB1 treated MSCs to enhance the engraftment potential of hematopoietic stem cells (HSCs). This initial observation will now be mechanistically dissected. In the proposed project, we will investigate whether expanded HSCs can also be enhanced in their transplantation efficiency. This would have a major impact on bone marrow transplantation in general, as well as for the use of HSCs in gene therapy in particular.

• DFG Programme: Research Grants