The role of anti-fibrotic macrophages in scar free repair and regeneration.

• Applicant: Dr. Nadjib Dastagir
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery ; Nephrology
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 425047824

The lack of scar-free healing and regeneration in humans imposes severe limitations on functional recovery after major traumatic injury, surgical interventions and disease. Default wound-repair in most adult human tissues initiates the formation of a protein/carbohydrate fibrotic network that progressively matures into dysfunctional scar tissue. In organs like the heart, lung and liver, formation of scar tissue can be deadly and contributes to ~45% of all U.S. deaths. Development of therapies that activate regeneration and scar-free repair programs in humans will transform modern healthcare. In contrast to humans and most other mammals, salamanders are capable of scar-free regeneration of almost all complex tissues including the limbs, heart, brain and spinal cord. Using the salamander as a model system, we recently demonstrated for the first time the critical role of the innate immune system in regulating scar-free regeneration. Specifically, we showed 1) that early infiltration of macrophages into damaged limb or heart tissue actively suppresses fibrosis and 2) that suppression of fibrosis is an essential step required for normal regeneration to occur. The cellular and molecular mechanisms by which macrophages suppress fibrosis after injury are completely unknown. The overarching goal of this proposal is to begin defining these mechanisms for the first-time using salamander limb regeneration as a model system. This project will be the first to define how salamander macrophages suppress myofibroblast induction and scar tissue formation. We will define the macrophage subtypes that can inhibit myofibroblast induction and fibrotic activation signals and perform gene expression analysis to begin identifying novel anti-fibrotic candidate molecules. Finally, testing the hypothesis that permanent scar-tissue formation in macrophage depleted limbs may be reversible by inhibition of lysyl oxidase, will allow dissection of key elements of the scarring response. These aims will provide the first mechanistic insights into macrophage support of scar-free healing.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor James Godwin, Ph.D.