Highly reproducible extracellular vesicles from rejuvenated mesenchymal progenitor cells

• Applicant: Privatdozentin Dr. Solvig Diederichs
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery ; Cell Biology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 569654430

Mesenchymal stromal cells (MSCs) have demonstrated high potential for cell therapy and tissue regeneration due to their paracrine activity. Exosomes, a subclass of extracellular vesicles (EVs) with a diameter of 30 to 150 nm, are the main paracrine effectors that mediate cell-to-cell communication. There are already compelling reports demonstrating the high potential of MSC-derived exosomes as a novel cell-free therapeutic approach in translational medicine. However, MSCs from human bone marrow cannot be standardized as an EV-producing cell source for clinical applications due to their cellular heterogeneity, high donor variability, and limited proliferation and differentiation capacity. Considering the technical and ethical issues associated with aspirating MSCs from patient bone marrow, alternative approaches have recently been developed that use induced pluripotent stem cells (iPSCs) and mesenchymal progenitors (iMPs) derived from them. The unlimited proliferation and differentiation potential acquired during reprogramming to pluripotency allows iPS cells to generate consistent and highly reproducible EV-producing cells, unlike MSCs. As iPSC progeny, iMPs resemble MSCs in terms of characteristic surface markers and the ability to differentiate in osteogenic, adipogenic, and chondrogenic directions; on the other hand, they retain a high proliferation potential from iPSCs. Thus, iMPs are ideal candidates that combine the advantages of iPSCs and MSCs while overcoming their disadvantages. Currently, there are only a very limited number of studies investigating the signaling activity and regenerative potential of iMP-EVs. Therefore, the question of their consistent and reproducible generation and their therapeutic potential remains open. We hypothesize that iMP-EVs can be produced with high reproducibility by standardizing culture and purification methods and that they can inhibit osteoarthritis-driving signaling pathways as well as have chondroprotective effects. With equal signaling activity, their reproducibility would surpass that of adult bone marrow MSC-EVs, thus outperforming these highly variable sEVs. Therefore, the aim of this project is to reproducibly produce iMP-EVs and investigate their ability to modulate osteoarthritis-relevant signaling pathways both in vitro and in vivo. We aim to compare EVs formed by iMPs with those formed by earlier mesodermal progenitors. We plan to use various biochemical and functional assays to demonstrate the consistency of their basic properties and signaling activity, as well as to provide initial preclinical data on their intra-articular application using a highly versatile biomaterial platform.

• DFG Programme: Research Grants