The role of cellular senescence in bone regeneration

• Applicants: Dr. Björn Fischer-Zirnsak, since 3/2020; Dr. Sven Geißler
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: from 2014 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 249509554

Excessive amounts of senescent cells are associated with aging, impaired tissue repair and deterioration of organ function. However, senescent cells also promote health span since they prevent malignant transformation and support regeneration by modulating inflammatory responses. We found that the lack of senescent cells compromises fracture repair, which underlines their importance for successful healing. The effects of senescent cells on their environment are partially mediated by secreted factors (senescence associated secretory phenotype, SASP). Similarly, mesenchymal stromal cells (MSCs) not only directly contribute to tissue formation during healing, but also shape regenerative processes via paracrine signals. Using MSCs with induced senescence and a premature aging mouse model (GorabPrx1), we identified two components of the SASP that influence osteogenesis: firstly decorin-regulated signaling and secondly CD73-mediated purinergic signaling. We now aim to elaborate how both pathways are influenced by cellular senescence and elucidate their general impact on MSC differentiation and their immunomodulatory properties. Concurrently with in vitro experiments, we aim to employ a humanized xenotransplantation model to further evaluate our findings in a controlled in vivo situation. The most promising target for improved fracture healing will subsequently be tested in our established osteotomy model. In summary, we want to learn from the nature of the senescence phenotype to take therapeutic advantage of those parts which are positive for (bone) regeneration, but overcome the disadvantages compromising new tissue formation.

• DFG Programme: Research Units
• Subproject of: FOR 2165: Regeneration in Aged Individuals: Using Bone Healing as a Model System to Characterise Regeneration under Compromised Conditions
• Ehemaliger Antragsteller: Professor Dr. Uwe Kornak, until 3/2020