Abstract
Mucopolysaccharidosis type I (MPS IH; Hurler syndrome) is a congenital deficiency of α-L-iduronidase, leading to lysosomal storage of glycosaminoglycans that is ultimately fatal following an insidious onset after birth. Hematopoietic cell transplantation (HCT) is a life-saving measure in MPS IH. However, because a suitable hematopoietic donor is not found for everyone, because HCT is associated with significant morbidity and mortality, and because there is no known benefit of immune reaction between the host and the donor cells in MPS IH, gene-corrected autologous stem cells may be the ideal graft for HCT. Thus, we generated induced pluripotent stem cells from 2 patients with MPS IH (MPS-iPS cells). We found that α-L-iduronidase was not required for stem cell renewal, and that MPS-iPS cells showed lysosomal storage characteristic of MPS IH and could be differentiated to both hematopoietic and nonhematopoietic cells. The specific epigenetic profile associated with de-differentiation of MPS IH fibroblasts into MPS-iPS cells was maintained when MPS-iPS cells are gene-corrected with virally delivered α-L-iduronidase. These data underscore the potential of MPS-iPS cells to generate autologous hematopoietic grafts devoid of immunologic complications of allogeneic transplantation, as well as generating nonhematopoietic cells with the potential to treat anatomical sites not fully corrected with HCT.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Bone Marrow Cells / cytology
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Bone Marrow Cells / metabolism
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Cell Differentiation*
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Cells, Cultured
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Child, Preschool
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DNA Methylation
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HEK293 Cells
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Hematopoietic System / cytology*
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Hematopoietic System / metabolism
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Iduronidase / genetics
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Iduronidase / metabolism
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Induced Pluripotent Stem Cells / cytology*
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Induced Pluripotent Stem Cells / metabolism
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Infant
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Keratinocytes / cytology
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Keratinocytes / metabolism
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Kruppel-Like Factor 4
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Kruppel-Like Transcription Factors / genetics
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Kruppel-Like Transcription Factors / metabolism
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Male
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Mesoderm / cytology
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Mesoderm / metabolism
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Mice
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Mucopolysaccharidosis I / genetics
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Mucopolysaccharidosis I / metabolism
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Mucopolysaccharidosis I / pathology
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Nanog Homeobox Protein
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Octamer Transcription Factor-3 / genetics
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Octamer Transcription Factor-3 / metabolism
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Promoter Regions, Genetic / genetics
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism
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SOXB1 Transcription Factors / genetics
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SOXB1 Transcription Factors / metabolism
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Stromal Cells / cytology
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Stromal Cells / metabolism
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Transfection
Substances
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Homeodomain Proteins
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Kruppel-Like Factor 4
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Kruppel-Like Transcription Factors
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MYC protein, human
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NANOG protein, human
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Nanog Homeobox Protein
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Octamer Transcription Factor-3
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POU5F1 protein, human
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Proto-Oncogene Proteins c-myc
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SOX2 protein, human
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SOXB1 Transcription Factors
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Iduronidase