Defining the immune-stem cell programs that drive multi-tissue regeneration in mammals

About This Grant

Project Summary Tissue regeneration represents a frontier in immunology: how immune cells coordinate the rebuilding of complex tissues after injury. While lower vertebrates regenerate entire appendages, mammals heal through inflammatory scarring, a process orchestrated by immune programs that remain poorly defined. This proposal aims to uncover how immune and stem cell interactions determine whether mammalian tissues regenerate or scar, and how these programs deteriorate with age. Our central hypothesis is that the immune system encodes a regenerative “decision code” through temporally and spatially coordinated cellular programs that license stem cells for multi-tissue regrowth. To test this, we will dissect two complementary mammalian models where regenerative outcomes diverge within the same tissue context. Aim 1 will identify the immune circuits that enable digit tip regeneration using intravital two-photon microscopy, single-cell and spatial transcriptomics, and targeted pathway perturbations. Aim 2 will define how age and injury context reshape immune regulation of regeneration in the mouse ear pinna, integrating in vivo photolabeling, optogenetic control of immune gene function, and high-dimensional immune– stromal network mapping. This project introduces a new immunological framework for regeneration, applying next- generation tools including custom-built multiphoton imaging, 4D single-cell profiling, and light- inducible gene editing to visualize and manipulate immune control of tissue repair in living mammals. By defining the immune programs that distinguish regeneration from scarring, this work will establish the immune system as a master regulator of regenerative capacity and reveal molecular targets to restore repair in aged or chronically inflamed tissues. These insights will transform how we understand and therapeutically harness immunity for tissue renewal.