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• W2799306261 abstract "Recessive dystrophic epidermolysis bullosa (RDEB) is caused by loss-of-function mutations in COL7A1 encoding type VII collagen (C7) that forms anchoring fibrils (AFs), structures essential for dermal-epidermal adherence (Uitto et al., 2017Uitto J. Has C. Vahidnezhad H. Youssefian L. Bruckner-Tuderman L. Molecular pathology of the basement membrane zone in heritable blistering diseases: the paradigm of epidermolysis bullosa.Matrix Biol. 2017; 57–58: 76-85Crossref PubMed Scopus (41) Google Scholar). Patients with RDEB suffer from skin and mucosal blistering and develop severe complications including invasive squamous cell carcinoma, resulting in a poor prognosis (Guerra et al., 2017Guerra L. Odorisio T. Zambruno G. Castiglia D. Stromal microenvironment in type VII collagen-deficient skin: the ground for squamous cell carcinoma development.Matrix Biol. 2017; 63: 1-10Crossref PubMed Scopus (65) Google Scholar). Different therapeutic strategies have been explored, including gene-, protein-, cell-based, and pharmacological therapies that have shown promising preclinical or transitory clinical benefits (Rashidghamat and McGrath, 2017Rashidghamat E. McGrath J.A. Novel and emerging therapies in the treatment of recessive dystrophic epidermolysis bullosa.Intractable Rare Dis Res. 2017; 6: 6-20Crossref PubMed Scopus (63) Google Scholar). To date, there is no specific treatment for RDEB. Bone marrow–mesenchymal stromal cells (BM-MSCs) have shown therapeutic potential for RDEB patients through BM transplantation and intradermal (ID) and intravenous injections (Conget et al., 2010Conget P. Rodriguez F. Kramer S. Allers C. Simon V. Palisson F. et al.Replenishment of type VII collagen and re-epithelialization of chronically ulcerated skin after intradermal administration of allogeneic mesenchymal stromal cells in two patients with recessive dystrophic epidermolysis bullosa.Cytotherapy. 2010; 12: 429-431Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, El-Darouti et al., 2016El-Darouti M. Fawzy M. Amin I. Abdel Hay R. Hegazy R. Gabr H. et al.Treatment of dystrophic epidermolysis bullosa with bone marrow non-hematopoeitic stem cells: a randomized controlled trial.Dermatol Ther. 2016; 29: 96-100Crossref PubMed Scopus (48) Google Scholar, Petrof et al., 2015Petrof G. Lwin S.M. Martinez-Queipo M. Abdul-Wahab A. Tso S. Mellerio J.E. et al.Potential of systemic allogeneic mesenchymal stromal cell therapy for children with recessive dystrophic epidermolysis bullosa.J Invest Dermatol. 2015; 135: 2319-2321Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, Tamai et al., 2011Tamai K. Yamazaki T. Chino T. Ishii M. Otsuru S. Kikuchi Y. et al.PDGFRα-positive cells in bone marrow are mobilized by high mobility group box 1 (HMGB1) to regenerate injured epithelia.Proc Natl Acad Sci USA. 2011; 108: 6609-6614Crossref PubMed Scopus (179) Google Scholar, Tolar et al., 2009Tolar J. Ishida-Yamamoto A. Riddle M. McElmurry R.T. Osborn M. Xia L. et al.Amelioration of epidermolysis bullosa by transfer of wild-type bone marrow cells.Blood. 2009; 113: 1167-1174Crossref PubMed Scopus (139) Google Scholar, Wagner et al., 2010Wagner J.E. Ishida-Yamamoto A. McGrath J.A. Hordinsky M. Keene D.R. Woodley D.T. et al.Bone marrow transplantation for recessive dystrophic epidermolysis bullosa.N Engl J Med. 2010; 363: 629-639Crossref PubMed Scopus (265) Google Scholar). Human bone marrow–mesenchymal stromal cells (hBM-MSCs) form a heterogeneous cell population that can self-renew or differentiate into mesenchymal lineages (Caplan, 1991Caplan A.I. Mesenchymal stem cells.Orthop Res. 1991; 9: 641-650Crossref PubMed Scopus (3473) Google Scholar). hBM-MSCs display properties that could potentially improve wound healing in RDEB: immunomodulation; anti-inflammatory, angiogenic, and antifibrotic properties; secretion of trophic factors; improvement of tissue repair; and the capacity to induce protein expression in the host tissues through a paracrine effect (Nuschke, 2014Nuschke A. Activity of mesenchymal stem cells in therapies for chronic skin wound healing.Organogenesis. 2014; 10: 29-37Crossref PubMed Scopus (129) Google Scholar, Qi et al., 2014Qi Y. Jiang D. Sindrilaru A. Stegemann A. Schatz S. Treiber N. et al.TSG-6 released from intradermally injected mesenchymal stem cells accelerates wound healing and reduces tissue fibrosis in murine full-thickness skin wounds.J Invest Dermatol. 2014; 134: 526-537Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar). Herein, we assessed the long-term capacity of hBM-MSCs to survive, produce, and deposit C7 at the dermal-epidermal junction (DEJ) after ID injection into human RDEB skin equivalents (SEs) transplanted onto immune-deficient nude mice that reproduce the skin defect observed in RDEB (Titeux et al., 2010Titeux M. Pendaries V. Zanta-Boussif M.A. Decha A. Pironon N. Tonasso L. et al.SIN retroviral vectors expressing COL7A1 under human promoters for ex vivo gene therapy of recessive dystrophic epidermolysis bullosa.Mol Ther. 2010; 18: 1509-1518Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). Phenotypic analyses of hBM-MSCs from healthy donors showed that they were positive for well-established surface markers (CD105, CD90, CD73, CD29, and CD44) and negative for potential hematopoietic contaminants (HLA-DR and CD45) (see Supplementary Figure S1 online). The capacity of these hBM-MSCs to differentiate in vitro into osteoblasts, adipocytes, and chondrocytes was previously shown (Peltzer et al., 2015Peltzer J. Montespan F. Thepenier C. Boutin L. Uzan G. Rouas-Freiss N. et al.Heterogeneous functions of perinatal mesenchymal stromal cells require a preselection before their banking for clinical use.Stem Cells Dev. 2015; 24: 329-344Crossref PubMed Scopus (25) Google Scholar). Then, we compared COL7A1 expression in hBM-MSCs from several donors cultured with 5% human platelet lysate or 10% fetal calf serum (see Supplementary Figure S2a and b online). C7 expression by hBM-MSCs from donor 1 was similar to human healthy fibroblasts when grown in human platelet lysate, whereas hBM-MSCs from other donors showed lower amounts of C7 (see Supplementary Figure S2c, d, and e). We next tested the capacity of hBM-MSCs to synthesize C7 able to form AF structures in vivo in a xenograft model. We ID injected hBM-MSCs beneath RDEB SE completely devoid of C7 expression (see Supplementary Figure S3 online), thus excluding any possible paracrine effect of hBM-MSCs on hRDEB fibroblasts and/or keratinocytes, leading to increased production of endogenous mutant C7. The dose of 2 × 106 of hBM-MSC was chosen based on a previous preclinical study (Kuhl et al., 2015Kuhl T. Mezger M. Hausser I. Handgretinger R. Bruckner-Tuderman L. Nystrom A. High local concentrations of intradermal MSCs restore skin integrity and facilitate wound healing in dystrophic epidermolysis bullosa.Mol Ther. 2015; 23: 1368-1379Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). We collected SE samples from the injected area at 1, 2, 4, and 6 months after treatment. Immunofluorescence staining of SE sections showed linear staining of human C7 (see Supplementary Figure S4 online) along the DEJ up to 6 months in healthy SEs and in hBM-MSC–injected RDEB SEs, whereas vehicle-injected RDEB SEs showed no detectable C7 staining (Figure 1a). Semiquantitative analysis of C7 fluorescence signal showed that hBM-MSC injection induced a significant increase in C7 deposition (up to 30%–40% of the level of healthy control SE) compared with vehicle-injected RDEB SE (Figure 1c), which is considered to be sufficient to prevent loss of dermal-epidermal adhesion (Fritsch et al., 2008Fritsch A. Loeckermann S. Kern J.S. Braun A. Bosl M.R. Bley T.A. et al.A hypomorphic mouse model of dystrophic epidermolysis bullosa reveals mechanisms of disease and response to fibroblast therapy.J Clin Invest. 2008; 118: 1669-1679Crossref PubMed Scopus (169) Google Scholar). Similar results were observed after injection of hBM-MSCs from donor 5 in RDEB SEs (see Supplementary Figure S5 online). Transmission electron microscopy showed the presence of AFs up to 6 months with typical loop-shaped structures inserted into the lamina densa in ID hBM-MSC–injected RDEB SEs and in healthy SEs, but no AF structures were found in vehicle-injected RDEB SEs (Figure 1b). Morphometric analyses showed a significant increase of AF number, especially at 2 months, a time when AF density was similar to healthy SE (95% of healthy control) (Figure 1d, and see Supplementary Figure S6 online). The fate of injected hBM-MSCs in the RDEB SEs was assessed by fluorescent in situ hybridization using probes specific for human X and Y chromosomes (see Supplementary Figure S7 online), because RDEB SEs were made from human female cells and were injected with hBM-MSCs arising from a human male donor. Fluorescent in situ hybridization analysis showed the presence of human X-Y chromosome–positive cells in the dermis at 1, 2, and 4 months after injection. No X-Y chromosome–positive cells were found in the dermis of RDEB SE 6 months after injection (Figure 2a). Therefore, injected hBM-MSCs were observed in the dermis of RDEB SEs up to 4 months after injection, but their number clearly diminished over time (Figure 2b). Immunofluorescence staining of the active cleaved caspase-3 showed that hBM-MSC–injected RDEB SEs displayed numerous apoptotic cells in the dermis from 2 to 4 months (Figure 2c), whereas no cells were detected in vehicle-injected RDEB SEs. The number of apoptotic cells expanded up to 4 months and decreased at 6 months, suggesting that most of the injected hBM-MSCs underwent apoptosis between 2 and 4 months after injection (Figure 2d). Previous RDEB studies using hBM-MSCs showed restoration of C7 at the DEJ for at least 12 weeks, although C7 production decreased over time (Conget et al., 2010Conget P. Rodriguez F. Kramer S. Allers C. Simon V. Palisson F. et al.Replenishment of type VII collagen and re-epithelialization of chronically ulcerated skin after intradermal administration of allogeneic mesenchymal stromal cells in two patients with recessive dystrophic epidermolysis bullosa.Cytotherapy. 2010; 12: 429-431Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, Kuhl et al., 2015Kuhl T. Mezger M. Hausser I. Handgretinger R. Bruckner-Tuderman L. Nystrom A. High local concentrations of intradermal MSCs restore skin integrity and facilitate wound healing in dystrophic epidermolysis bullosa.Mol Ther. 2015; 23: 1368-1379Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). We show a longer effect of hBM-MSCs on C7 production and AF formation (up to 6 months). This is likely due to the extended survival time of injected hBM-MSCs (up to 4 months) compared with the 28 days previously reported (Kuhl et al., 2015Kuhl T. Mezger M. Hausser I. Handgretinger R. Bruckner-Tuderman L. Nystrom A. High local concentrations of intradermal MSCs restore skin integrity and facilitate wound healing in dystrophic epidermolysis bullosa.Mol Ther. 2015; 23: 1368-1379Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar), attributable to the lack of immune rejection in our immune-deficient model. Localized ID injections and the survival of injected hBM-MSCs may represent limitations to treating all symptoms of RDEB. However, ID injections could be repeated over time to sustain clinical benefit in RDEB patients. In addition, systemic delivery of hBM-MSCs could be envisaged, although the extent to which systemic delivery of hBM-MSCs allows engraftment of injected cells in the skin and restoration of C7 is not known (Webber et al., 2017Webber B.R. O’Connor K.T. McElmurry R.T. Durgin E.N. Eide C.R. Lees C.J. et al.Rapid generation of Col7a1(-/-) mouse model of recessive dystrophic epidermolysis bullosa and partial rescue via immunosuppressive dermal mesenchymal stem cells.Lab Invest. 2017; 97: 1218-1224Crossref PubMed Scopus (23) Google Scholar). Therefore, if the treatment has to be repeated for a long period, the risk of allo-reactions to allogeneic hBM-MSCs through the semidirect allorecognition pathway (Alegre et al., 2016Alegre M.L. Lakkis F.G. Morelli A.E. Antigen presentation in transplantation.Trends Immunol. 2016; 37: 831-843Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar) may impair the efficacy of these approaches. An alternative would be to use gene-corrected autologous hBM-MSCs to improve persistence of injected cells and to allow repeated injections. This study was conducted in accordance with ethical principles stated in the Declaration of Helsinki. Patient consent for experiments was not required, because the French law considers human tissue left over from surgery as discarded material. The mice experiments were performed in compliance with guidelines for animal experiments in France and were approved by the local animal research ethics committee. The authors state no conflict of interest. This work was supported by grants from the Institut National de la Santé et de la Recherche Médicale (INSERM) and Dystrophic Epidermolysis Bullosa Association (DEBRA) France. The project was granted by a PhD fellowship from the French Ministry of Education, Sciences and Technologies. We thank Araksya Izmiryan, Nathalie Pironon, and Sabine Duchatelet for technical advices. The authors acknowledge Alain Schmitt from Cochin Institute TEM facility for processing skin for transmission electron microscopy analyses and Valérie Malan from the Cytogenetic Department, Necker Hospital for Sick Children, Paris, France. We also acknowledge the Cell Imaging and Animal facilities from Imagine Institute, Paris, France. Download .pdf (.92 MB) Help with pdf files Supplementary Data" @default.
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• W2799306261 date "2018-11-01" @default.
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• W2799306261 title "Intradermal Injection of Bone Marrow Mesenchymal Stromal Cells Corrects Recessive Dystrophic Epidermolysis Bullosa in a Xenograft Model" @default.
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