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Updated: Mar 31, 2026
Development and Identification of a Novel Subpopulation of Human Neutrophil-derived Giant Phagocytes In Vitro
Published on: January 25, 2017
The natural behavior of mononuclear phagocytes in HTS formation
Zhensen Zhu1,2, Jie Ding1, Zengshuan Ma1
1Division of Plastic and Reconstructive Surgery, Wound Healing Research Group, University of Alberta, Edmonton, Alberta, Canada.
Abstract:
Hypertrophic scars (HTS) are caused by trauma or burn injuries to the deep dermis and are considered fibrosis in the skin. Monocytes, M1 and M2 macrophages are mononuclear phagocytes. Studies suggest that M2 macrophages are profibrotic and might contribute to HTS formation. Our lab has established a human HTS-like nude mouse model, in which the grafted human skin develops red, raised, and firm scarring, resembling HTS seen in humans. In this study, we observed the natural behavior of mononuclear phagocyte system in this nude mouse model of dermal fibrosis at multiple time points. Thirty athymic nude mice received human skin grafts and an equal number of mice received mouse skin grafts as controls. The grafted skin and blood were harvested at 1, 2, 3, 4, and 8 weeks. Wound area, thickness, collagen morphology and level, the cell number of myofibroblasts, M1- and M2-like macrophages in the grafted skin, as well as monocyte fraction in the blood were investigated at each time points. Xenografted mice developed contracted and thickened scars grossly. The xenografted skin resembled human HTS tissue based on enhanced thickness, fibrotic orientation of collagen bundles, increased collagen level, and infiltration of myofibroblasts. In the blood, monocytes dramatically decreased at 1 week postgrafting and gradually returned to normal in the following 8 weeks. In the xenografted skin, M1-like macrophages were found predominantly at 1-2 weeks postgrafting; whereas, M2-like macrophages were abundant at later time points, 3-4 weeks postgrafting coincident with the development of fibrosis in the human skin tissues. This understanding of the natural behavior of mononuclear phagocytes in vivo in our mouse model provides evidence for the role of M2-like macrophages in fibrosis of human skin and suggests that macrophage depletion in the subacute phases of wound healing might reduce or prevent HTS formation.
Insights
M2 macrophages are abundant in later stages of wound healing, contributing to hypertrophic scar (HTS) formation. Targeting these macrophages in subacute phases may prevent HTS development.
Area of Science:
- Dermatology
- Immunology
- Wound Healing Research
Background:
- Hypertrophic scars (HTS) result from deep dermal trauma or burns and are a form of skin fibrosis.
- M2 macrophages are implicated in profibrotic processes and may play a role in HTS development.
Purpose of the Study:
- To investigate the in vivo behavior of mononuclear phagocytes in a humanized mouse model of dermal fibrosis.
- To understand the temporal dynamics of macrophage subtypes and their correlation with scar formation.
Main Methods:
- A human hypertrophic scar-like nude mouse model was established using human skin xenografts.
- Analysis of grafted skin and blood was performed at multiple time points (1, 2, 3, 4, and 8 weeks postgrafting).
- Evaluated parameters included wound characteristics, collagen deposition, myofibroblasts, M1/M2 macrophages, and blood monocyte levels.
Main Results:
- Xenografted mice developed thickened, contracted scars resembling human HTS.
- Monocyte levels in blood decreased significantly at 1 week postgrafting, gradually normalizing.
- M1 macrophages predominated early (1-2 weeks), while M2 macrophages increased later (3-4 weeks), coinciding with fibrosis.
Conclusions:
- The study provides in vivo evidence for the role of M2-like macrophages in human skin fibrosis within the established mouse model.
- Modulating macrophage populations, specifically depleting M2 macrophages during subacute wound healing, could be a therapeutic strategy to prevent HTS.
