Vitamin A–coupled liposomes containing siRNA against HSP47 ameliorate skin fibrosis in chronic graft-versus-host disease

• Published in: Blood Vol. 131; no. 13; pp. 1476 - 1485
• Main Authors: Yamakawa, Tomohiro, Ohigashi, Hiroyuki, Hashimoto, Daigo, Hayase, Eiko, Takahashi, Shuichiro, Miyazaki, Miyono, Minomi, Kenjiro, Onozawa, Masahiro, Niitsu, Yoshiro, Teshima, Takanori
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.03.2018
• Subjects: Allografts; Animals; Chronic Disease; Collagen; Female; Fibrosis; Graft vs Host Disease - drug therapy; Graft vs Host Disease - genetics; Graft vs Host Disease - pathology; Hematopoietic Stem Cell Transplantation; HSP47 Heat-Shock Proteins - antagonists & inhibitors; HSP47 Heat-Shock Proteins - genetics; HSP47 Heat-Shock Proteins - metabolism; Liposomes; Macrophages - metabolism; Macrophages - pathology; Mice; Mice, Inbred BALB C; Myofibroblasts - metabolism; Myofibroblasts - pathology; RNA, Small Interfering - genetics; RNA, Small Interfering - pharmacology; Skin Diseases - drug therapy; Skin Diseases - genetics; Skin Diseases - metabolism; Skin Diseases - pathology; Vitamin A - pharmacology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2017-04-779934

Chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (SCT) is characterized by multiorgan fibrosis and profoundly affects the quality of life of transplant survivors. Heat shock protein 47 (HSP47), a collagen-specific molecular chaperone, plays a critical role in collagen synthesis in myofibroblasts. We explored the role of HSP47 in the fibrotic process of cutaneous chronic GVHD in mice. Immunohistochemical analysis showed massive fibrosis with elevated amounts of collagen deposits and accumulation of F4/80+ macrophages, as well as myofibroblasts expressing HSP47 and retinol-binding protein 1 in the skin after allogeneic SCT. Repeated injection of anti–colony-stimulating factor (CSF-1) receptor-blocking antibodies significantly reduced HSP47+ myofibroblasts in the skin, indicating a macrophage-dependent accumulation of myofibroblasts. Vitamin A-coupled liposomes carrying HSP47 small interfering RNA (siRNA) (VA-lip HSP47) delivered HSP47 siRNA to cells expressing vitamin A receptors and knocked down their HSP47 in vitro. Intravenously injected VA-lip HSP47 were specifically distributed to skin fibrotic lesions and did not affect collagen synthesis in healthy skin. VA-lip HSP47 knocked down HSP47 expression in myofibroblasts and significantly reduced collagen deposition without inducing systemic immunosuppression. It also abrogated fibrosis in the salivary glands. These results highlight a cascade of fibrosis in chronic GVHD; macrophage production of transforming growth factor β mediates fibroblast differentiation to HSP47+ myofibroblasts that produce collagen. VA-lip HSP47 represent a novel strategy to modulate fibrosis in chronic GVHD by targeting HSP47+ myofibroblasts without inducing immunosuppression. •HSP47+ myofibroblasts are accumulated in the fibrotic lesions of chronic GVHD and promote fibrosis in a CSF-1R+ macrophage-dependent manner.•Vitamin A–coupled liposomes containing HSP47 siRNA abrogate HSP47 expression in myofibroblasts and ameliorate fibrosis in chronic GVHD.