title: Mechanisms of fibroblast cell therapy for dystrophic epidermolysis bullosa: high stability of collagen VII favors long-term skin integrity.
abstract: Here, we report on the first systematic long-term study of fibroblast therapy in a mouse model for recessive dystrophic epidermolysis bullosa (RDEB), a severe skin-blistering disorder caused by loss-of-function of collagen VII. Intradermal injection of wild-type (WT) fibroblasts in >50 mice increased the collagen VII content at the dermal-epidermal junction 3.5- to 4.7-fold. Although the active biosynthesis lasted <28 days, collagen VII remained stable and dramatically improved skin integrity and resistance to mechanical forces for at least 100 days, as measured with a digital 3D-skin sensor for shear forces. Experiments using species-specific antibodies, collagen VII-deficient fibroblasts, gene expression analyses, and cytokine arrays demonstrated that the injected fibroblasts are the major source of newly deposited collagen VII. Apart from transitory mild inflammation, no adverse effects were observed. The cells remained within an area <or=10 mm of the injection site, and did not proliferate, form tumors, or cause fibrosis. Instead, they became gradually apoptotic within 28 days. These data on partial restoration of collagen VII in the skin demonstrate the excellent ratio of clinical effects to biological parameters, support suitability of fibroblast-based therapy approaches for RDEB, and, as a preclinical test, pave way to human clinical trials.
authors: Deparment of Dermatology, University Medical Center Freiburg, Freiburg, Germany.
authors: Johannes S
authors: JS
authors: Kern
authors: Stefan
authors: S
authors: Loeckermann
authors: Anja
authors: A
authors: Fritsch
authors: Ingrid
authors: I
authors: Hausser
authors: Wera
authors: W
authors: Roth
authors: Thomas M
authors: TM
authors: Magin
authors: Claudia
authors: C
authors: Mack
authors: Marcel L
authors: ML
authors: Müller
authors: Oliver
authors: O
authors: Paul
authors: Patrick
authors: P
authors: Ruther
authors: Leena
authors: L
authors: Bruckner-Tuderman
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D002478:Cells, Cultured; D024143:Collagen Type VII / Q000378:metabolism*; D016108:Epidermolysis Bullosa Dystrophica / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D005434:Flow Cytometry; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000378:metabolism / Q000473:pathology*
chemical_list: D024143:Collagen Type VII