98.10 - Deletion of Neuropilin-1 in the Epidermis Delays Wound Healing
Saturday, April 2, 2022
12:41 PM – 12:44 PM
Room: 118 BC - Pennsylvania Convention Center
Introduction: Session Description: As a Society, we cannot escape the identity crisis we have confronted in the past - what is pathology and how do pathologists fit into the basic framework of biomedical science? This is an ongoing challenge that requires our members to educate others regarding the nature of the discipline of experimental pathology and how our research describes and investigates the pathology, pathogenesis, and pathophysiology of specific diseases at the molecular, cellular, organ, and organismal level. Overcoming this identity crisis requires effort on the part of each ASIP member and our success will be evident as we continue to attract bright and enthusiastic young investigators into the diverse field of experimental pathobiology.
The American Society for Investigative Pathology presents I Am An ASIP Member and This Is My Science a dynamic and inspiring session featuring ASIP Scientists on the Cutting Edge of Discovery briefly, present their research, accomplishments, career journeys, and service to ASIP. This session highlights the diversity among our membership, and provides trainees, young scientists, pathologists, and the members of the larger scientific community the opportunity to become inspired by Trailblazers in the field of investigative pathology.
Sausan Alfaris (Boston Childrens Hospital, Harvard School of Dental Medicine), Asma Almazyad (Boston Childrens Hospital, Harvard School of Dental Medicine), Joud Omari (Boston Childrens Hospital, Harvard School of Dental Medicine), Yao Gao (Boston Childrens Hospital, Harvard Medical School), Dakshnapriya Balasubbramanian (Boston Childrens Hospital, Harvard Medical School), Diane Bielenberg (Boston Childrens Hospital, Harvard Medical School)
Presenting Author Boston Childrens Hospital, Harvard School of Dental Medicine
When cutaneous tissue is exposed to trauma it undergoes complex biological processes to achieve healing. Our goal is to better understand the cellular pathways and molecular mechanisms that control wound healing. Upon injury to the skin, cells in the epidermis and dermis secrete a number of cytokines and growth factors to promote cell survival, proliferation, and migration. Hepatocyte growth factor (HGF) is a protein secreted from fibroblasts that has been shown to function in several different stages of wound healing, including re-epithelialization. HGF and its tyrosine kinase receptor MET are upregulated in various phases of the healing cascade such as in the wound epidermis as well as in granulation tissue and blood vessels. Previous studies have shown that the transmembrane glycoprotein Neuropilin-1 (Nrp1) acts as a co-receptor for HGF (in addition to VEGF) in endothelial cells, while our laboratory has shown that Nrp1 is constitutively expressed in keratinocytes and its expression is up-regulated following stress (such as after UV-irradiation). However, the role of Nrp1 in epithelial cells or in the wound healing process, and its contribution to epidermal HGF/MET signaling is unclear. We hypothesized that Nrp1 cooperates with MET to signal via HGF to promote epithelial proliferation and improve wound healing. Adult male and female transgenic mice (K14-creERT;Nrp1f/f) were either untreated (Controls; n=10 mice/group) or treated with tamoxifen to delete Nrp1 in keratinocytes (K14-iNrp1-KO; n=10 mice/group). Two weeks later, mice received full-thickness dermal punch biopsies on their shaved dorsum. Wounds were measured daily and wound areas were graphed and compared. At select time points, additional wounded mice were euthanized and tissues were embedded for histologic examination. Our results indicate that under basal conditions, Nrp1 deletion in the epidermis does not affect the number or differentiation status of keratinocytes as K14-iNrp1-KO mice skin was equal in thickness and morphology to control littermates. However, upon injury, wound closure rates were significantly slower in male K14-iNrp1-KO mice compared to female K14-iNrp1-KO mice or Controls. In summary, absence of Nrp1 in the epidermis causes delays in wound healing indicating that Nrp1 plays a significant role in re-epithelialization. Ongoing studies are investigating the activation of MET by HGF following Nrp1 silencing in epithelial cells to decipher the co-receptor dependency of MET on Nrp1. These findings may lead to an improved understanding of the wound healing process and suggest targets for future drug development.
King Faisal Specialist Hospital and Research Centre: Full scholarship for graduate education and training (S.A.); NHLBI R01HL141858 (D.R.B); Vascular Biology Program, Boston Childrens Hospital (D.R.B)
