Division of Hematology-Oncology, Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota 55455, USA.
J Invest Dermatol. 2011 Apr;131(4):848-56. doi: 10.1038/jid.2010.346. Epub 2010 Dec 2.
Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited blistering skin disorder caused by mutations in the COL7A1 gene-encoding type VII collagen (Col7), the major component of anchoring fibrils at the dermal-epidermal junction. Individuals with RDEB develop painful blisters and mucosal erosions, and currently, there are no effective forms of therapy. Nevertheless, some advances in patient therapy are being made, and cell-based therapies with mesenchymal and hematopoietic cells have shown promise in early clinical trials. To establish a foundation for personalized, gene-corrected, patient-specific cell transfer, we generated induced pluripotent stem (iPS) cells from three subjects with RDEB (RDEB iPS cells). We found that Col7 was not required for stem cell renewal and that RDEB iPS cells could be differentiated into both hematopoietic and nonhematopoietic lineages. The specific epigenetic profile associated with de-differentiation of RDEB fibroblasts and keratinocytes into RDEB iPS cells was similar to that observed in wild-type (WT) iPS cells. Importantly, human WT and RDEB iPS cells differentiated in vivo into structures resembling the skin. Gene-corrected RDEB iPS cells expressed Col7. These data identify the potential of RDEB iPS cells to generate autologous hematopoietic grafts and skin cells with the inherent capacity to treat skin and mucosal erosions that typify this genodermatosis.
隐性营养不良型大疱性表皮松解症（RDEB）是一种遗传性水疱性皮肤病，由 COL7A1 基因突变引起，该基因突变编码 VII 型胶原（Col7），是真皮-表皮连接锚定纤维的主要成分。患有 RDEB 的个体易出现疼痛性水疱和黏膜糜烂，目前尚无有效的治疗方法。然而，一些患者治疗方面取得了一些进展，间充质和造血细胞的基于细胞的治疗在早期临床试验中显示出了前景。为了为个性化、基因矫正、患者特异性细胞转移建立基础，我们从三个 RDEB 患者中生成了诱导多能干细胞（iPS 细胞）（RDEB iPS 细胞）。我们发现 Col7 对于干细胞更新不是必需的，并且 RDEB iPS 细胞可以分化为造血和非造血谱系。与 RDEB 成纤维细胞和角质细胞去分化为 RDEB iPS 细胞相关的特定表观遗传谱与观察到的 WT iPS 细胞相似。重要的是，WT 和 RDEB iPS 细胞在体内分化为类似于皮肤的结构。基因矫正的 RDEB iPS 细胞表达 Col7。这些数据表明 RDEB iPS 细胞具有生成自体造血移植物和皮肤细胞的潜力，这些细胞具有治疗这种遗传性皮肤病典型的皮肤和黏膜糜烂的固有能力。
