Grants We Funded

Abstract

Impact Statement: The novelty of the project will be the identification of the fibroblast population responsible for facial scarring and oral regeneration in murine and human skin. Moreover, we will characterize the cell surface markers for isolating and enriching the scarring fibroblast and oral regenerative population. Using single-RNA sequencing of the cell transcriptome, we will determine the signaling pathways that regulate the functional activity of the scarring and regenerative fibroblasts, providing new innovative molecular approaches to reverse facial scarring. More importantly, we will develop therapeutic platforms to study facial scarring, paving the way for investigation into fibrotic conditions of the head and neck where fibrosis is central including burns, radiation and tumour progression.

Project Summary: Skin scarring causes substantial functional and aesthetic consequences for patients and is especially detrimental in the setting of craniofacial repair. Scars on the face arise commonly following trauma, burns and surgery. Despite the wide prevalence of scars, there is no current effective treatment to prevent or reverse the fibrotic process in skin. Development of new approaches to facial scarring has been delayed due to the lack of clear understanding into the key cell types and molecular processes that contribute to craniofacial fibrosis. Cutaneous fibroblasts are the central cell involved in fibrosis, synthesizing excessive extracellular matrix to form scars. While fibroblasts were long believed to be a fairly homogenous cell population, recent work has shown a striking heterogeneity of fibroblasts within the skin. Our group has previously shown that embryonic En1 expression marks a distinct lineage of fibroblasts in the mouse dorsal skin that causes scar formation. Scarring in the craniofacial region is not uniform. While injuries to the facial skin heal by scarring, the oral cavity heals with a different phenotype. Wounds to the oral mucosa heal with minimal to no scar, regenerating tissue that is indistinguishable from unwounded oral mucosa. However, the fibroblast subpopulation that is responsible for facial scarring and oral regeneration has not been identified. Furthermore, the limited progress into the identification of the fibroblast responsible for skin scarring has been hindered further due to the absence of cell surface markers to distinguish specific fibroblast subpopulations. Our proposed project aims to identify and characterize the fibroblast subpopulation responsible for facial scar formation and oral regeneration in a mouse model. We will characterize the cell surface markers and signaling pathways that allow for the identification and isolation of the fibroblast scarring and oral regenerative population, providing therapeutic targets to reverse or prevent facial scarring. To ensure rapid translation of our findings to the clinical setting we will isolate and characterize the scarring fibroblast population responsible for fibrosis in human orofacial skin using a novel xenograft model. Elucidation of the cellular and molecular mechanisms of scar formation, will provide novel insights into fibrosis that can be applied to developing therapies to promote regeneration and reverse facial scaring.

Biography
I am currently working as postdoctoral research scholar in the Dr Longaker laboratory at Stanford University. I have extensive basic science research experience due to the accumulation of two master’s degrees, PhD and protected research time as an academic third year resident in plastic surgery in the UK. I have a passion and strong research interest for utilizing tissue engineering approaches to improve the care given to plastic surgery patients living with craniofacial deformities. During my PhD, I developed a new synthetic biomaterial for cartilage replacement that passed all preclinical evaluations for human use and is being translated to the clinical setting as a new implant for craniofacial reconstruction. The Hagey Laboratory has a world renown reputation and leading in the field of skin scarring, developing novel molecular targets to treat and reverse fibrosis. To develop my knowledge and experience in utilizing tissue engineering and regenerative medicine strategies to improve patient care in plastic surgery, I chose Stanford University for my postdoctoral training. My project will build upon my experience in tissue engineering and the overlapping research interest of Stanford University in craniofacial wound healing and fibrosis. Having already successfully completed fellowship grants to timelines and budgets, I have the experience and expertise to work independently and collaborate with team members to drive the project forward to completion.