title: Bone marrow monocyte lineage cells adhere on injured endothelium in a monocyte chemoattractant protein-1-dependent manner and accelerate reendothelialization as endothelial progenitor cells.
abstract: Peripheral blood (PB)-derived CD14+ monocytes were shown to transdifferentiate into endothelial cell (EC) lineage cells and contribute to neovascularization. We investigated whether bone marrow (BM)- or PB-derived CD34-/CD14+ cells are involved in reendothelialization after carotid balloon injury. Although neither hematopoietic nor mesenchymal stem cells were included in human BM-derived CD34-/CD14+ monocyte lineage cells (BM-MLCs), they expressed EC-specific markers (Tie2, CD31, VE-cadherin, and endoglin) to an extent identical to mature ECs. When BM-MLCs were cultured with vascular endothelial growth factors, hematopoietic markers were drastically decreased and new EC-specific markers (Flk and CD34) were induced. BM-MLCs were intra-arterially transplanted into balloon-injured arteries of athymic nude rats. When BM-MLCs were activated by monocyte chemoattractant protein-1 (MCP-1) in vivo or in vitro, they adhered onto injured endothelium, differentiated into EC-like cells by losing hematopoietic markers, and inhibited neointimal hyperplasia. Ability to prevent neointimal hyperplasia was more efficient than that of BM-derived CD34+ cells. MCP-dependent adhesion was not observed in PB-derived CD34-/CD14+ monocytes. Regenerated endothelium exhibited a cobblestone appearance, blocked extravasation of dye, and induced NO-dependent vasorelaxation. Basal adhesive activities on HUVECs under laminar flow and beta1-integrin expression (basal and active forms) were significantly increased in BM-MLCs compared with PB-derived monocytes. MCP-1 markedly enhanced adhesive activity of BM-MLCs (2.8-fold) on HUVECs by activating beta1-integrin conformation. Thus, BM-MLCs can function as EC progenitors that are more potent than CD34+ cells and acquire the ability to adhere on injured endothelium in a MCP-1-dependent manner, leading to reendothelialization associated with inhibition of intimal hyperplasia. This will open a novel window to MCP-1-mediated biological actions and vascular regeneration strategies by cell therapy.
authors.affiliation: Department of Medicine II, Kansai Medical University, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Fujiyama
authors.forename: Katsuya
authors.initials: K
authors.lastname: Amano
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Uehira
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yoshida
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Nishiwaki
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Nozawa
authors.forename: Denan
authors.initials: D
authors.lastname: Jin
authors.forename: Shinji
authors.initials: S
authors.lastname: Takai
authors.forename: Mizuo
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Kensuke
authors.initials: K
authors.lastname: Egashira
authors.forename: Takayuki
authors.initials: T
authors.lastname: Imada
authors.forename: Toshiji
authors.initials: T
authors.lastname: Iwasaka
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsubara
mesh_terms: D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis; D001854:Bone Marrow Cells / Q000166:cytology*; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D042783:Endothelial Cells / Q000502:physiology*; D004730:Endothelium, Vascular / Q000276:immunology / Q000293:injuries / Q000502:physiology*; D018014:Gene Transfer Techniques; D006801:Humans; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D051381:Rats; D011923:Rats, Nude; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*
chemical_list: D000943:Antigens, Differentiation; D018932:Chemokine CCL2