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

Yamakawa, Tomohiro; Ohigashi, Hiroyuki; Hashimoto, Daigo; Hayase, Eiko; Takahashi, Shuichiro; Miyazaki, Miyono; Minomi, Kenjiro; Onozawa, Masahiro; Niitsu, Yoshiro; Teshima, Takanori

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

Yamakawa, Tomohiro; Ohigashi, Hiroyuki; Hashimoto, Daigo et al.

Blood, 2018, 131(13), 1476-1485

Permalink : https://hdl.handle.net/2115/73341

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論文情報

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アクセス権	open access
URI	https://hdl.handle.net/2115/73341
タイトル	Vitamin A–coupled liposomes containing siRNA against HSP47 ameliorate skin fibrosis in chronic graft-versus-host disease
著者	Yamakawa, Tomohiro ; Ohigashi, Hiroyuki ; Hashimoto, Daigo ; Hayase, Eiko ; Takahashi, Shuichiro ; Miyazaki, Miyono ; Minomi, Kenjiro ; Onozawa, Masahiro ; Niitsu, Yoshiro ; Teshima, Takanori
著者名 Yamakawa, Tomohiro
著者名 Ohigashi, Hiroyuki
e-Rad_Researcher 20419576 著者名 Hashimoto, Daigo
著者名 Hayase, Eiko
著者名 Takahashi, Shuichiro
著者名 Miyazaki, Miyono
著者名 Minomi, Kenjiro
e-Rad_Researcher 70455632 著者名 Onozawa, Masahiro
著者名 Niitsu, Yoshiro
e-Rad_Researcher 40284096 著者名 Teshima, Takanori
言語	英語
発行日	2018-03-29
出版者	American Society of Hematology
収録物名	Blood
巻(号)	131(13)
ページ	1476-1485
抄録	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.
資源タイプ	学術雑誌論文
出版タイプ	Version of Record
PISSN	0006-4971
関連情報 (isIdenticalTo)	出版社版DOI https://doi.org/10.1182/blood-2017-04-779934