Defining the role of catecholaminergic neurons in wound healing

The National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases awarded Yale University $228,900 under Project Grant F32AR087195 on November 16, 2026, to investigate the role of catecholaminergic neurons in wound healing and their dysfunction under diabetic conditions. The research, which extends through May 31, 2029, will determine how nerve endings within the skin contribute to wound healing through intercellular communication in vivo and how this process fails in diabetic patients, who face up to 25% lifetime risk of developing chronic non-healing wounds. The project employs skin as a model for studying innervation's role in tissue regeneration using genetic mouse models and targeted neuronal manipulation, building on preliminary findings that skin-resident neurons transiently facilitate wound healing and that pharmacological denervation impairs the repair process. Work is performed in New Haven, Connecticut.

Abstract

As the primary barrier between the body and the environment, mammalian skin is highly heterogeneous, and densely innervated, enabling the sensations of touch, temperature, and pain in response to injury. Post injury, successful skin regeneration requires the precise spatial and temporal organization of multiple cell types and their ability to communicate with one another. When these processes are disrupted, the skin fails to regenerate leading to chronic wound formation. One specific population in which this is often observed is those with diabetes, with up to 25% of diabetic patients also developing a chronic non-healing wound in their lifetime. In addition to chronic wounding, diabetes is also associated with neuropathies or nerve damage. Yet, whether these complications are intertwined or how neurons in the skin may regulate regeneration remains unclear. Therefore, the overall goal of this proposal is to determine how nerve endings found within the skin contribute to the wound healing process through intercellular communication in vivo, and how this process goes awry under diabetic conditions. Skin serves as an excellent model for studying the role of innervation in tissue regeneration, due to its accessibility for imaging, well defined stages of repair, and availability of genetic mouse models and tools that allow for targeted manipulation of specific neuronal subsets within IT. Recently, our lab uncovered the unexpected transient role of skin resident neurons during skin injury repair. Robust nerve bundles are observed within the wound bed as early as 24 hours post injury. However, as healing progresses and additional cell types infiltrate the damaged area, these nerve bundles are depleted from the regenerating tissue. Furthermore, pharmacologically depleting the skin of its innervation impairs the wound healing process. Together, this data suggesting a critical role of skin resident neurons during the skin regeneration. In aim 1, i will define the class and function of skin resident neurons involved in normal and diabetic wound repair. Using tissue clearing techniques, whole mount and live imaging, pharmacological approaches to target specific subtypes of neurons, and various genetic mouse models, i will generate a comprehensive view neuronal dynamics during wound healing. In aim 2, i will delineate the mechanisms in which neurons communicate to other cell types in the niche to regulate wound healing. By employing RNA sequencing, fiber photometry, and in vitro assays, i will identify signaling pathways and secretory factors involved in neuron mediated wound repair. Together, these studies will provide significant insight into the neuronal populations involved in skin regeneration and identify potential therapeutic targets for enhancing wound healing in diabetic patients.