My laboratory recently uncovered an unexpected and intriguing role for a specific population of monocyte-derived cells during skin wound healing. In particular, we identified that CD301b+ cells, which is expressed by a subset of monocyte-derived cells including dendritic cells and macrophages, are essential for skin wound healing including regeneration of dermal adipocytes. Our findings are important for several reasons. First, heterogeneity and plasticity with populations of monocyte-derived cells have been recently discovered and which cell type is essential for promoting skin wound healing is not known. Second, our data reveal an essential role for a subclass of monocyte-derived cells that express CD301b in skin wound repair. Finally, monocytes and their derivatives are a tractable cell type to create a personalized therapy to promote healing in patients with chronic wounds. Through three focused and complementary Specific Aims, the work proposed in this application will take advantage of multiple genetic mouse models that allow specific depletion of monocyte derivatives, transplantation assays, cell culture models, and a novel bioanalytical assay platform to identify the secretome of individual monocytes isolated from the skin. We will (1) identify the role of specific populations of monocyte- derived cells during skin wound healing, (2) analyze the function of the secretome of monocyte-derived cells in controling dermal wound healing, and (3) define whether specific monocyte-derived cell populations function in defective wounds of aged and diabetic mice. These studies will identify specific pro-healing cell populations that can be utilized to promote healing in human patients with defective wound healing or other skin disorders.

Public Health Relevance

A thorough understanding of cells and molecules that regulate skin wound healing is essential for the generation of tissue-specific regenerative therapies to effectively treat human disease. Since the manner in which specific populations of monocyte-derived cells function during skin wound healing is largely unknown, we will define how these major but poorly understood cells function during skin wound healing. Our work will improve our understanding of the cells and molecules that control basic skin regeneration, how monocyte-derived cells function in this process, and will have global relevance for other regenerative tissues that require monocyte-derived cells.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Arthritis, Connective Tissue and Skin Study Section (ACTS)
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Belkin, Alexey
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Yale University
Schools of Arts and Sciences
New Haven
United States
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Shook, Brett A; Wasko, Renee R; Rivera-Gonzalez, Guillermo C et al. (2018) Myofibroblast proliferation and heterogeneity are supported by macrophages during skin repair. Science 362:
Zwick, Rachel K; Guerrero-Juarez, Christian F; Horsley, Valerie et al. (2018) Anatomical, Physiological, and Functional Diversity of Adipose Tissue. Cell Metab 27:68-83
Rivera-Gonzalez, Guillermo C; Shook, Brett A; Horsley, Valerie (2017) PDGFA regulation of dermal adipocyte stem cells. Stem Cell Investig 4:72