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(Circulation. 2004;110:2924-2930.)
© 2004 American Heart Association, Inc.

Transplantation

Stromal Cell–Derived Factor-1 and CXCR4 Interaction Is Critical for Development of Transplant Arteriosclerosis

Hideyasu Sakihama, MD; Taro Masunaga, PhD; Kenichiro Yamashita, MD; Taku Hashimoto, MD; Manabu Inobe, MD; Satoru Todo, MD; Toshimitsu Uede, MD, PhD

From the Division of Molecular Immunology (H.S., T.M., M.I., T.U.), Institute for Genetic Medicine, and First Department of Surgery (H.S., K.Y., T.H., S.T.), Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

Correspondence to Toshimitsu Uede, MD, PhD, Division of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, N-15, W-7, Kita-ku, Sapporo 060-0815, Japan. E-mail toshi{at}imm.hokudai.ac.jp

Received November 18, 2003; de novo received March 15, 2004; revision received June 4, 2004; accepted June 7, 2004.

Background— Posttransplant chronic allograft deterioration associated with development of transplant arteriosclerosis (TA) remains an unresolved problem. Recent studies suggest that the smooth muscle cells (SMCs) constituting the neointima are derived from recipient hematopoietic stem cells (HSCs). However, the underlying mechanisms of the process are not yet fully elucidated.

Methods and Results— We examined the genes expressed in allografts at different stages of TA development using a mice aortic transplantation model. Genes were analyzed by a differential mRNA display technique. We show that stromal cell–derived factor-1 (SDF-1) is a critical molecular target for the treatment of TA. During the course of TA, intragraft SDF-1 expression was upregulated with time, and the circulating HSCs expressing its counterreceptor CXCR4 increased in the recipients receiving allografts. CXCR4-positive HSCs, derived from transplant recipients, migrated into allografts via microvessels in the adventitia and then toward the luminal side. The HSCs differentiated into SMC-like cells, contributing to the in situ formation of the neointima. In support of a functional role for these molecules, in vivo neutralization of SDF-1 inhibited HSC mobilization and significantly attenuated neointimal formation.

Conclusions— Interaction between SDF-1 and CXCR4 plays a key role in TA development. Blockade of SDF-1 may become a new therapeutic modality for TA.

Key Words: transplantation • arteriosclerosis • rejection • stem cells

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