Spatial genomics of musculoskeletal regeneration in a translational mouse model of premature aging
Description: Delayed fracture healing and non-unions account for 5 – 10% of all bone fractures and present a challenging problem in regenerative medicine, particularly in elderly osteoporotic patients. Bone regeneration is a mechano-sensitive process; thus, different mechanical stimuli can either enhance or impair regeneration. However, the underlying molecular mechanisms by which mechanical stimuli locally alter cellular behaviour are complex and poorly understood, which has prevented wider-scale harnessing of the mechano-sensitivity of the regenerative process in clinical applications. Understanding these molecular mechanisms of mechanically-regulated tissue formation is therefore crucial to create optimal healing environments for different bone fractures. Genome-wide association studies (GWAS) have identified novel factors underlying specific organ-level phenotypes and diseases, e.g. senile osteoporosis. During aging, point mutations and deletions of mitochondrial DNA (mtDNA) accumulate in a variety of tissues in diverse species (e.g. humans, rodents). DNA polymerase ? (Polg) is uniquely responsible for all DNA synthetic reactions including both replication and repair of mtDNA. Hence, the PolgA(D257A/D257A) mouse model, characterized by elevated mtDNA point mutations and systemic mitochondrial dysfunction, exhibits an accelerated aging phenotype (e.g. weight loss, alopecia). Our previous studies showed female PolgA mice display frailty, osteosarcopenia and reduced mechanosensitivity with age.The overall objectives of the proposed project are to develop a molecular-based spatio-temporal understanding of musculoskeletal mechanobiology during regeneration and to investigate how this mechano-sensitivity is compromised with age. Via a cross-disciplinary approach (micro-FE-based individualized femur defect loading model, time-lapsed in vivo micro-CT, spatial single cell transcriptomics of the callus and the surrounding muscle), the project aims (I) to link the transcriptome of single cells in the fracture callus and the surrounding muscle to their local mechanical in vivo environment (LivE), (II) to investigate molecular responses of single cells at the injury site to LivE changes with aging and (III) to achieve a systems level understanding of the spatio-temporal regulation of gene expression during the process of load-induced bone regeneration in the aging mouse. Detailed understanding of the spatio-temporal molecular mechanisms governing load-regulated bone regeneration will help to identify novel molecular therapeutic targets for age-related impaired fracture healing.
Amount: CHF 160,000
Funding type: research
Funder scheme: COST (European Cooperation in Science and Technology)
Start date: 2021-01-01
End date: 2022-12-31
Investigator: Müller, Ralph
Institution: ETH Zurich – ETHZ
Funded outputs count: 5
Funder award ID: 198152
OpenAlex ID: G6952069969