Abnormal wound healing responses, which include both chronic non-healing wounds and excessive dermal scarring, result in significant morbidity and healthcare expenditures in the United States and worldwide. The extracellular matrix (ECM) plays a critical role in wound repair through regulation of cell migration, differentiation, proliferation, and survival, as well as bioavailability of growth factors. Although type III collagen (Col3), a component of the ECM, is assumed to play an important role in wound repair due to its increased expression early in this process, its precise role has remained enigmatic. Our studies indicate that Col3 has a key role in wound healing, distinct from type I collagen (Col1). Specifically, our in vitro and in vivo published and preliminary data provide evidence that Col3 regulates reparative cell activities and fate by 1) altering ECM organization and structure to direct mechanical communication between cells and the matrix; 2) promoting keratinocyte migration to improve reepithelialization; and 3) limiting scar formation by suppressing the differentiation and persistence of myofibroblasts, the fibrogenic cells of the wound. Additional preliminary data support that Col3 suppresses myofibroblast differentiation via 4) binding and sequestering the profibrogenic cytokine transforming growth factor ? (TGF?) through its N-propeptide, and 5) altering integrin function. The central hypothesis of this proposal is that Col3 directs reparative cell activities and fate to maximize a regenerative response following cutaneous injury. Our goal is to define the structural and cellular mechanisms of Col3, and to demonstrate the efficacy of Col3-containing biomaterials to enhance a regenerative response during wound healing. We propose to accomplish this goal through three major aims: to determine the impact of Col3 on the collagen fibrous network to modulate collagen fibril characteristics, covalent intermolecular cross-linking, and viscoelastic properties during scar evolution and to direct keratinocyte migration (Aim 1), to determine the role of Col3 in the differentiation and persistence of fibrogenic myofibroblasts, specifically its impact on integrin signaling and profibrotic growth factor availability (Aim 2), and to demonstrate the potential for exogenous Col3 to rejuvenate healing in an impaired murine wound healing model and to limit scar formation following cutaneous injury in a preclinical porcine model (Aim 3). Improving our understanding of how Col3 directs a regenerative response during cutaneous wound repair has the potential to identify new anti-fibrotic therapies for other pathologies such as pulmonary and renal fibrosis and hepatic cirrhosis;
our third aim will also enable us to apply our findings more immediately to a translatable and safe intervention to treat debilitating chronic wounds and minimize pathologic scarring. As such, we anticipate it will have a significant impact on human health.

Public Health Relevance

Disorders of wound healing, including chronic non-healing wounds and excessive scarring, are a major cause of suffering and healthcare costs worldwide. We have shown that the extracellular matrix (ECM) protein type III collagen (Col3) plays an important role in promoting wound healing while reducing scar formation. Our proposed experiments will investigate how Col3 regulates cell activities by mediating their interactions with the ECM and soluble factors in the healing environment and will determine whether Col3, if delivered to wounds, can improve wound healing outcomes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM124091-01A1
Application #
9661674
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2018-09-21
Project End
2023-08-31
Budget Start
2018-09-21
Budget End
2019-08-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104