Our overall goal is to understand how the dermal and epidermal compartments communicate during wound repair. Wound healing requires orchestrated repopulation and regeneration of the lost tissue, a process deficient in normal aging, after large traumatic or burn wounds, and in numerous chronic diseases. In skin wounds, fibroblasts are recruited to regenerate the dermal layer, and keratinocytes from the margins to re-epithelialize the initial clot. Orchestration of repair is conducted by signals from successive waves of growth factor, chemokines, and matrix fragments. A central question is how cells in the different compartments communicate or sense the status of the healing. For instance, how does a dermal fibroblast 'know' that re-epithelialization is complete and thus must switch to the resolving phase functions of contraction and collagen remodeling? Soluble peptide factors play major roles in signaling cell proliferation and migration into the wound and differentiation functions including wound contraction and epidermal stratification. Prominent during all stages of wound repair are epidermal growth factor receptor ligands that induce fibroblast and keratinocyte motility and proliferation. However, the equally important 'stop' and differentiation signals have not been fully elucidated. We have posited a novel model in which ELR- CXC chemokines (PF4, IP-10, MIG and IP-9) are elaborated to limit or modulate the responses to growth factors. Our previous studies determined that these chemokines negatively regulate fibroblast repopulation and steer these cells to more reparative phase contraction. Recently, we found that, surprisingly, these same chemokines promote proliferation and migration of mesenchymally-transitioned keratinocytes, the differentiation state that is responsible for re-epithelialization. We hypothesize that during wound repair, the dermal compartment is synchronized to re-epithelialization status by IP-9. The following hypotheses will test this model: I. That 1P-9 is a wound-response factor produced during re-epithelialization. We will identify the source and stimulus for IP-9 production and whether re-epithelialization is prerequisite for production. II. That 1P-9 is a keratinocyte-derived factor that alters fibroblast and keratinocyte repopulation. We will identify the intracellular signaling pathways it evokes in fibroblasts and keratinocytes. Ill. That IP-9 and 1P-10 alter fibroblast and keratinocyte functioning and differentiation state. This will be determined in vitro and then verified in targeted transgenic mice. The completion of these investigations will yield a model of dermal skin repair in which key extracellular and intracellular molecules are identified that can be targeted to either increase healing or limit scarring.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM063569-03
Application #
6912677
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Ikeda, Richard A
Project Start
2003-07-01
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
3
Fiscal Year
2005
Total Cost
$236,931
Indirect Cost
Name
University of Pittsburgh
Department
Pathology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Bradshaw, Andrew; Sylakowski, Kyle; Wells, Alan (2018) The Pro-reparative Engine: Stem Cells Aid Healing by Dampening Inflammation. Curr Pathobiol Rep 6:109-115
Shao, Hanshuang; Wang, Anna; Lauffenburger, Douglas et al. (2018) Tyro3-mediated phosphorylation of ACTN4 at tyrosines is FAK-dependent and decreases susceptibility to cleavage by m-Calpain. Int J Biochem Cell Biol 95:73-84
Wells, Alan; Wiley, H Steven (2018) A systems perspective of heterocellular signaling. Essays Biochem 62:607-617
Yates, Cecelia C; Rodrigues, Melanie; Nuschke, Austin et al. (2017) Multipotent stromal cells/mesenchymal stem cells and fibroblasts combine to minimize skin hypertrophic scarring. Stem Cell Res Ther 8:193
Shao, Hanshuang; Lauffenburger, Douglas; Wells, Alan (2017) Tyro3 carboxyl terminal region confers stability and contains the autophosphorylation sites. Biochem Biophys Res Commun 490:1074-1079
Yates, Cecelia C; Nuschke, Austin; Rodrigues, Melanie et al. (2017) Improved Transplanted Stem Cell Survival in a Polymer Gel Supplemented With Tenascin C Accelerates Healing and Reduces Scarring of Murine Skin Wounds. Cell Transplant 26:103-113
Wells, Alan; Nuschke, Austin; Yates, Cecelia C (2016) Skin tissue repair: Matrix microenvironmental influences. Matrix Biol 49:25-36
Bodnar, Richard J; Satish, Latha; Yates, Cecelia C et al. (2016) Pericytes: A newly recognized player in wound healing. Wound Repair Regen 24:204-14
Nuschke, Austin; Rodrigues, Melanie; Wells, Albin W et al. (2016) Mesenchymal stem cells/multipotent stromal cells (MSCs) are glycolytic and thus glucose is a limiting factor of in vitro models of MSC starvation. Stem Cell Res Ther 7:179
Nuschke, Austin; Rodrigues, Melanie; Rivera, Jaime et al. (2016) Epidermal Growth Factor Tethered to ?-Tricalcium Phosphate Bone Scaffolds via a High-Affinity Binding Peptide Enhances Survival of Human Mesenchymal Stem Cells/Multipotent Stromal Cells in an Immune-Competent Parafascial Implantation Assay in Mice. Stem Cells Transl Med 5:1580-1586

Showing the most recent 10 out of 41 publications