title: Bone marrow cell transfer into fetal circulation can ameliorate genetic skin diseases by providing fibroblasts to the skin and inducing immune tolerance.
abstract: Recent studies have shown that skin injury recruits bone marrow-derived fibroblasts (BMDFs) to the site of injury to accelerate tissue repair. However, whether uninjured skin can recruit BMDFs to maintain skin homeostasis remains uncertain. Here, we investigated the appearance of BMDFs in normal mouse skin after embryonic bone marrow cell transplantation (E-BMT) with green fluorescent protein-transgenic bone marrow cells (GFP-BMCs) via the vitelline vein, which traverses the uterine wall and is connected to the fetal circulation. At 12 weeks of age, mice treated with E-BMT were observed to have successful engraftment of GFP-BMCs in hematopoietic tissues accompanied by induction of immune tolerance against GFP. We then investigated BMDFs in the skin of the same mice without prior injury and found that a significant number of BMDFs, which generate matrix proteins both in vitro and in vivo, were recruited and maintained after birth. Next, we performed E-BMT in a dystrophic epidermolysis bullosa mouse model (col7a1(-/-)) lacking type VII collagen in the cutaneous basement membrane zone. E-BMT significantly ameliorated the severity of the dystrophic epidermolysis bullosa phenotype in neonatal mice. Type VII collagen was deposited primarily in the follicular basement membrane zone in the vicinity of the BMDFs. Thus, gene therapy using E-BMT into the fetal circulation may offer a potential treatment option to ameliorate genetic skin diseases that are characterized by fibroblast dysfunction through the introduction of immune-tolerated BMDFs.
authors.affiliation: Division of Gene Therapy Science, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Takenao
authors.initials: T
authors.lastname: Chino
authors.forename: Katsuto
authors.initials: K
authors.lastname: Tamai
authors.forename: Takehiko
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Satoru
authors.initials: S
authors.lastname: Otsuru
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kikuchi
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nimura
authors.forename: Masayuki
authors.initials: M
authors.lastname: Endo
authors.forename: Miki
authors.initials: M
authors.lastname: Nagai
authors.forename: Jouni
authors.initials: J
authors.lastname: Uitto
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Kitajima
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kaneda
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods; D024143:Collagen Type VII / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000637:transplantation; D016108:Epidermolysis Bullosa Dystrophica / Q000628:therapy*; D005347:Fibroblasts / Q000166:cytology*; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000166:cytology* / Q000276:immunology
chemical_list: D024143:Collagen Type VII; D049452:Green Fluorescent Proteins