Abstract
Recent generation of patient-specific induced pluripotent stem cells (PS-iPSCs) provides significant advantages for cell- and gene-based therapy. Establishment of iPSC-based therapy for skin diseases requires efficient methodology for differentiating iPSCs into both keratinocytes and fibroblasts, the major cellular components of the skin, as well as the reconstruction of skin structures using these iPSC-derived skin components. We previously reported generation of keratinocytes from human iPSCs for use in the treatment of recessive dystrophic epidermolysis bullosa (RDEB) caused by mutations in the COL7A1 gene. Here, we developed a protocol for differentiating iPSCs into dermal fibroblasts, which also produce type VII collagen and therefore also have the potential to treat RDEB. Moreover, we generated in vitro 3D skin equivalents composed exclusively human iPSC-derived keratinocytes and fibroblasts for disease models and regenerative therapies for skin diseases, first demonstrating that iPSCs can provide the basis for modeling a human organ derived entirely from two different types of iPSC-derived cells.
Highlights
Induced pluripotent stem cells are stem cells generated from individual somatic cells by exogenous expression of several transcription factors to initiate the reprogramming process [1]
The generation of PS-Induced pluripotent stem cells (iPSCs) is expected to provide an autologous source of cells to develop patient-specific customized cell and gene therapy [2], in large part by coupling this approach with gene correction
Recent studies provided the first demonstrations of gene modification based on homologous recombination in ESCs and iPSCs using zinc-finger nucleases (ZFNs), a novel tool for gene modification which generates double-strand breaks at specific sites in the human genome [28]
Summary
Induced pluripotent stem cells (iPSCs) are stem cells generated from individual somatic cells by exogenous expression of several transcription factors to initiate the reprogramming process [1]. Autologous PS-iPSCs have the potential to provide an unlimited source of cells for gene and cell therapies for specific human diseases, since they are believed to have unlimited proliferative capacity and extensive differentiation capability into a wide range of cell types. Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited blistering disorder caused by mutations in the COL7A1 gene encoding type VII collagen, the major component of anchoring fibrils at the basement membrane zone (BMZ) at the epidermal-dermal junction of the skin. Since anchoring fibrils provide functional integrity to the skin, defective anchoring fibrils caused by lack or deficiency of type VII collagen leads to skin fragility. Patients with RDEB develop severe skin phenotypes, including repeated skin blistering from minor trauma, as well as mutilating scarring, alopecia, corneal erosions, tooth and nail dystrophy, esophageal strictures, joint contractures, and fusion of fingers and toes [3]. Since SCCs in patients with RDEB are highly aggressive and metastatic, SCCs are one of the most life-threatening complications for RDEB patients [4]
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