title: Transplanted bone marrow-derived circulating PDGFRα+ cells restore type VII collagen in recessive dystrophic epidermolysis bullosa mouse skin graft.
abstract: Recessive dystrophic epidermolysis bullosa (RDEB) is an intractable genetic blistering skin disease in which the epithelial structure easily separates from the underlying dermis because of genetic loss of functional type VII collagen (Col7) in the cutaneous basement membrane zone. Recent studies have demonstrated that allogeneic bone marrow transplantation (BMT) ameliorates the skin blistering phenotype of RDEB patients by restoring Col7. However, the exact therapeutic mechanism of BMT in RDEB remains unclear. In this study, we investigated the roles of transplanted bone marrow-derived circulating mesenchymal cells in RDEB (Col7-null) mice. In wild-type mice with prior GFP-BMT after lethal irradiation, lineage-negative/GFP-positive (Lin(-)/GFP(+)) cells, including platelet-derived growth factor receptor α-positive (PDGFRα(+)) mesenchymal cells, specifically migrated to skin grafts from RDEB mice and expressed Col7. Vascular endothelial cells and follicular keratinocytes in the deep dermis of the skin grafts expressed SDF-1α, and the bone marrow-derived PDGFRα(+) cells expressed CXCR4 on their surface. Systemic administration of the CXCR4 antagonist AMD3100 markedly decreased the migration of bone marrow-derived PDGFRα(+) cells into the skin graft, resulting in persistent epidermal detachment with massive necrosis and inflammation in the skin graft of RDEB mice; without AMD3100 administration, Col7 was significantly supplemented to ameliorate the pathogenic blistering phenotype. Collectively, these data suggest that the SDF1α/CXCR4 signaling axis induces transplanted bone marrow-derived circulating PDGFRα(+) mesenchymal cells to migrate and supply functional Col7 to regenerate RDEB skin.
authors.affiliation: Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan; Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan; Department of Dermatology, Asahikawa Medical College, Asahikawa 078-8510, Japan;
authors.forename: Shin
authors.initials: S
authors.lastname: Iinuma
authors.affiliation: Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan;
authors.forename: Eriko
authors.initials: E
authors.lastname: Aikawa
authors.affiliation: Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan; tamai@gts.med.osaka-u.ac.jp.
authors.forename: Katsuto
authors.initials: K
authors.lastname: Tamai
authors.affiliation: Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan;
authors.forename: Ryo
authors.initials: R
authors.lastname: Fujita
authors.affiliation: Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan;
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kikuchi
authors.affiliation: Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan;
authors.forename: Takenao
authors.initials: T
authors.lastname: Chino
authors.affiliation: Immunology and Cell Biology, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan;
authors.forename: Junichi
authors.initials: J
authors.lastname: Kikuta
authors.affiliation: Department of Molecular Dermatology, King's College, London WC2R 2LS, United Kingdom; and.
authors.forename: John A
authors.initials: JA
authors.lastname: McGrath
authors.affiliation: Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: Jouni
authors.initials: J
authors.lastname: Uitto
authors.affiliation: Immunology and Cell Biology, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan;
authors.forename: Masaru
authors.initials: M
authors.lastname: Ishii
authors.affiliation: Department of Dermatology, Asahikawa Medical College, Asahikawa 078-8510, Japan;
authors.forename: Hajime
authors.initials: H
authors.lastname: Iizuka
authors.affiliation: Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan;
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kaneda
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002469:Cell Separation; D054377:Chemokine CXCL12 / Q000378:metabolism; D024143:Collagen Type VII / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D016108:Epidermolysis Bullosa Dystrophica / Q000378:metabolism* / Q000473:pathology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D045164:Mesenchymal Stem Cell Transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D016038:Skin Transplantation
chemical_list: C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; D024143:Collagen Type VII; D019718:Receptors, CXCR4; D020796:Receptor, Platelet-Derived Growth Factor alpha