Plastic Surgery Research Council
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PSRC 60th Annual Meeting

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Morphologic And Histological Comparison Of Hypertrophic Scar In Nude And Knockout Mice Deficient In T, B And Natural Killer Cells
Moein Momtazi, BSc, MSc, MD.
University of Alberta, Edmonton, AB, Canada.

PURPOSE
Xenotransplantation of human skin onto nude mice results in proliferative scars with morphologic and histological similarities to human hypertrophic scar (HSc). These observations prompted us to consider strains of knockout mice to investigate the effects of deleting subsets of immune cells on proliferative scar formation.
Our objectives are:
1. Demonstrate that grafting human skin onto TCR (T-cell receptor) αβ-/-γδ-/-, RAG (recombination activating gene)-1-/- and RAG-2-/-γc-/- mice results in scars morphologically and histologically consistent with human HSc.
2. Characterize histologic and cellular changes that occur in scars with removal of specific immune cell subsets.
3. Compare scar response over time nude and knockout mice.
METHODS
Nude, TCRαβ-/-γδ-/-, RAG-1-/- and RAG-2-/-γc-/- mice (n=20 per strain) were xenografted with split thickness human skin and euthanized at 30, 60, 120 and 180 days postoperatively. Control animals (n=5 per strain) were autografted with full thickness mouse skin. Scar biopsies and normal skin were harvested at each time point. Sections were stained with hematoxylin and eosin (H & E), Masson’s trichrome and toluidine blue. Immunohistochemistry included anti-human HLA-ABC, α-smooth muscle actin (SMA), decorin and biglycan staining.
RESULTS
At 30 days post-operatively, xenografted nude, TCRαβ-/-γδ-/-, RAG-1-/- and RAG-2-/-γc-/- mice developed shiny, firm, elevated scars consistent with human. This scar morphology is in contrast to the flat, supple, inconspicuous scars observed in autografted controls. In nude mice, the average percent increase in scar thickness compared to the original skin graft was 254.0 ±7.4% (p<-0.01). Average percent increase in scar thickness for knockout animals was 265.3 ±10.8% for TCRαβ-/-γδ-/-, 164.7 ±10.2% for RAG-1-/- and 208.0 ±12.8% for RAG-2-/-γc-/- mice (p<0.01).

Histologically, scars from all four strains of mice are hypercellular, hypervascular, possess an abundance of disorganized, whorl-like collagen fibers and express less decorin compared to normal skin.


Positive staining for α-SMA expressing myofibroblasts, a pathognomonic feature of HSc was seen in all four strains over time. Compared to nude mice, knockout animals demonstrated a greater capacity for scar remodeling manifested by decreasing average scar thickness and alteration in α-SMA staining patterns over time.

Conclusion: Split thickness xenografts transplanted onto TCRαβ-/-γδ-/-, RAG-1-/- and RAG-2-/-γc-/- mice result in murine scars with morphologic and histologic features of human HSc. Remodeling of murine scars generated in knockout animals is analogous to changes known to occur in human HSc and suggests scars in these animal models may better represent the natural history of HSc.


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