Grants and Contributions:

Grant or Award spanning more than one fiscal year. (2017-2018 to 2022-2023)

Mammalian evolution has selected for accelerated wound closure at the expense of generating fibrotic scar. To enable future development of therapies that improve skin healing, a comprehensive understanding of the molecular signals that promote a regenerative versus fibrotic healing response will be essential. Our current understanding of these divergent processes is poor, partly because we lack a robust mammalian model of tissue regeneration.

Deer antlers are the only mammalian organ capable of complete regeneration. Growing antlers are covered in skin (velvet) that contains hair follicles, glands, dense innervation and vascular supply. In exciting preliminary work, we discovered that after injury, antler velvet is capable of scarless regeneration, a phenomenon previously ascribed only to embryonic skin. Regenerated velvet wounds contain newly formed hair follicles, glands, dense innervation and pigmentation. In contrast, identical wounds in backskin (of the same animal) resulted in fibrotic scar, consisting of disorganized extracellular matrix and an absence of appendages, innervation or pigment. We will exploit this powerful comparative model to study the basic cellular and molecular dynamics that underlie these divergent modes of mammalian skin repair. We will test the hypothesis that regeneration is enabled by a unique gene expression program within velvet dermal fibroblasts.

Aim 1- To characterize the molecular regulators that enable skin regeneration versus formation of fibrotic scar. We will use RNAseq to perform a comparative transcriptomic analysis of injured antler velvet and backskin to identify the molecular mechanisms that enable velvet regeneration.

Aim 2 – Functional evaluation of genes that are exclusively activated or repressed during velvet regeneration. Small molecules and lentiviral vectors designed to activate or inhibit identified genes or associated signaling pathways, will be applied to velvet and backskin wounds to ascertain their role in promoting regeneration or scar formation.

Aim 3 - To isolate and characterize dermal progenitors from antler velvet. We hypothesize that velvet is enriched with dermal progenitors that enable regeneration. We will isolate progenitors from antler velvet or backskin dermis/mesenchyme and perform phenotypic characterization and transplantation experiments to compare their intrinsic functional capacities.

Aim 4 – To characterize macrophage dynamics within resting antler velvet and during fibrotic skin repair versus regeneration. Macrophage are essential contributors to tissue regeneration. We hypothesize that macrophage exhibit a unique response to velvet injury which consequently modifies the dermal fibroblast repair program. Using immunostaining, cell sorting and cytometry we will document the composition of resident macrophages as well as the response to injury in backskin versus velvet.