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Originally published online as doi:10.2353/ajpath.2008.070977 on August 18, 2008 Originally published online as doi:10.2353/ajpath.2008.070977 on August 7, 2008

Published online before print August 7, 2008
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(American Journal of Pathology. 2008;173:803-814.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070977

Bone Marrow Cell Transfer into Fetal Circulation Can Ameliorate Genetic Skin Diseases by Providing Fibroblasts to the Skin and Inducing Immune Tolerance

Takenao Chino*{dagger}, Katsuto Tamai*, Takehiko Yamazaki*, Satoru Otsuru*, Yasushi Kikuchi*, Keisuke Nimura*, Masayuki Endo*, Miki Nagai{dagger}, Jouni Uitto{ddagger}, Yasuo Kitajima{dagger} and Yasufumi Kaneda*

From the Division of Gene Therapy Science,* Osaka University Graduate School of Medicine, Osaka, Japan; the Department of Dermatology,{dagger} Gifu University School of Medicine, Gifu, Japan; and the Department of Dermatology and Cutaneous Biology,{ddagger} Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania

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.






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Copyright © 2008 by the American Society for Investigative Pathology.