The process of wound healing is critical to restoring integrity and homeostasis after significant skin injuries. Although embryonic skin can heal by regenerating itself completely, adult skin is only capable of partial repair, altering the skin's integrity at the site of injury. Cutaneous adipose tissue is thought to poorly regenerate during wound healing, and because scars lack adipose tissue, they often assume debilitating hypertrophic, keloid, or atrophic characteristics. Lack of adipose regeneration is also a major cause of long term morbidity following extensive soft tissue trauma or surgical resection, such as tumor removal. We have identified the previously unknown phenomenon of adipose tissue neogenesis in large cutaneous wounds that occurs under the instructive signaling of de novo hair follicles. This application will focus on identifying permissive epigenetic changes and novel signaling cues generated by neogenic hair follicles in the wound environment that guide de novo regeneration of cutaneous fat. Our recent lineage analyses show that instead of recruiting already committed adipose precursors from the wound's edges and simply stimulating their differentiation to lipid-laden adipocytes, neogenic hair follicles guide de novo adipogenic cell fae acquisition by otherwise non-adipogenic wound myofibroblasts. Our studies demonstrate that acquisition of adipose identity by wound myofibroblasts critically depends on reactivation of Zfp423 signaling, the lead adipogenic commitment pathway in embryogenesis. Our studies also implicate hair follicle-derived BMP signaling inputs as the critical regulators of adipogenic fate commitment in wound scar tissue. The first goal of the proposed research is to establish the epigenetic changes in wound myofibroblasts that permit their adipogenic competence. Specifically, we will focus on epigenetic changes in Zfp423, the developmental master-regulator gene characterized by an exceptionally CpG-dense promoter. The second goal is to establish the mechanism by which BMP signaling events generated in the wound around neogenic hair follicles promote de novo fat formation. Ultimately, we want to be able to replicate these signaling events in hairless wounds for the purposes of inducing cutaneous fat regeneration. We anticipate that the proposed studies will help uncover new mechanisms that allow adult skin to expand lineage plasticity during wound repair. They could also have applicability to the development of new scarless wound healing strategies.

Public Health Relevance

Skin quickly loses its embryonic regeneration potential, and wound healing in adult skin yields fibrous scars. Adipose tissue, a normal component of the skin, is distinctly missing from cutaneous scars. This application will explore the previously unknown mechanism that enables adult skin to regenerate functional adipose tissue during wound healing, thereby opening new therapeutic possibilities for embryonic-like, scarless regeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR067273-02
Application #
8929930
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Tseng, Hung H
Project Start
2014-09-18
Project End
2019-08-31
Budget Start
2015-09-01
Budget End
2016-08-31
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92617
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Sun, Zheng; Plikus, Maksim V; Komarova, Natalia L (2016) Near Equilibrium Calculus of Stem Cells in Application to the Airway Epithelium Lineage. PLoS Comput Biol 12:e1004990
Chen, Chih-Chiang; Plikus, Maksim V; Tang, Pin-Chi et al. (2016) The Modulatable Stem Cell Niche: Tissue Interactions during Hair and Feather Follicle Regeneration. J Mol Biol 428:1423-40
Yang, Jienian; Plikus, Maksim V; Komarova, Natalia L (2015) The Role of Symmetric Stem Cell Divisions in Tissue Homeostasis. PLoS Comput Biol 11:e1004629

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