Bleomycin-induced Scleroderma in Nude Mice can be Reversed by Injection of Adipose Tissue: Evidence for a Novel Therapeutic Intervention in Systemic Sclerosis

Abstract

Objective: Systemic sclerosis is an autoimmune disease characterised by uncontrolled fibrosis and vascular insufficiency of the skin and internal organs, without efficient treatments. Subcutaneous adipose transplants have been shown to exert trophic effects on surrounding tissue. We aimed to determine the effects of human adipose tissue in a murine model of sclerotic skin. Methods: Scleroderma was induced in 48 nude mice by daily subcutaneous injection of bleomycin during four weeks. Immediately after the final bleomycin injection, human subcutaneous adipose tissue was implanted into the subcutaneous space of mice using either the Coleman method or the micro-injection method. Epidermal and dermal thicknesses were assessed on skin biopsy specimens six weeks after fat implantation. Capillary density was assessed using immunohistochemistry with an endothelial-specific marker (CD31). Results: Bleomycin increased dermal thickness (p<0.01), collagen network, and density of elastic fibers. Adipose tissue implantation reduced dermal thickness by 10% (p<0.01) with the Coleman method and by 14% (p<0.001) with the micro-injection method. Delivery of adipose tissue by the micro-injection method led to significantly greater neovascularization than the Coleman method (p<0.001). Conclusion: Implantation of human adipose tissue resulted in significant improvement of both fibrosis and peripheral vascular sufficiency in this mouse model of sclerotic skin. Use of a micro-injection method was associated with superior outcome. We postulate that this positive effect is likely due to the activity of the stromal vascular fraction found within adipose tissue. Thus, injection of autologous adipose tissue may be a promising novel therapy for patients with hand or perioral functional impairment.