Induced Pluripotent Stem Cells with a Mitochondrial DNA Deletion§

Authors

  • Anne B. C. Cherry,

    1. Division of Hematology/Oncology, Stem Cell Transplantation Program, Boston Children's Hospital, Boston, Massachusetts, USA
    2. Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA; Harvard Stem Cell Institute, Cambridge, Massachusetts, USA; Manton Center for Orphan Disease Research, Boston, Massachusetts, USA
    3. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA; Howard Hughes Medical Institute
    Search for more papers by this author
  • Katelyn E. Gagne,

    1. Division of Hematology/Oncology, Stem Cell Transplantation Program, Boston Children's Hospital, Boston, Massachusetts, USA
    2. Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA; Harvard Stem Cell Institute, Cambridge, Massachusetts, USA; Manton Center for Orphan Disease Research, Boston, Massachusetts, USA
    Search for more papers by this author
  • Erin M. Mcloughlin,

    1. Division of Hematology/Oncology, Stem Cell Transplantation Program, Boston Children's Hospital, Boston, Massachusetts, USA
    2. Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA; Harvard Stem Cell Institute, Cambridge, Massachusetts, USA; Manton Center for Orphan Disease Research, Boston, Massachusetts, USA
    3. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA; Howard Hughes Medical Institute
    Search for more papers by this author
  • Anna Baccei,

    1. Department of Newborn Medicine and Division of Genetics, Brigham and Women's Hospital; Department of Newborn Medicine, Boston Children's Hospital; Harvard Medical School, Boston, Massachusetts, USA
    Search for more papers by this author
  • Bryan Gorman,

    1. Department of Newborn Medicine and Division of Genetics, Brigham and Women's Hospital; Department of Newborn Medicine, Boston Children's Hospital; Harvard Medical School, Boston, Massachusetts, USA
    Search for more papers by this author
  • Odelya Hartung,

    1. Division of Hematology/Oncology, Stem Cell Transplantation Program, Boston Children's Hospital, Boston, Massachusetts, USA
    2. Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA; Harvard Stem Cell Institute, Cambridge, Massachusetts, USA; Manton Center for Orphan Disease Research, Boston, Massachusetts, USA
    Search for more papers by this author
  • Justine D. Miller,

    1. Division of Hematology/Oncology, Stem Cell Transplantation Program, Boston Children's Hospital, Boston, Massachusetts, USA
    2. Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA; Harvard Stem Cell Institute, Cambridge, Massachusetts, USA; Manton Center for Orphan Disease Research, Boston, Massachusetts, USA
    Search for more papers by this author
  • Jin Zhang,

    1. Division of Hematology/Oncology, Stem Cell Transplantation Program, Boston Children's Hospital, Boston, Massachusetts, USA
    2. Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA; Harvard Stem Cell Institute, Cambridge, Massachusetts, USA; Manton Center for Orphan Disease Research, Boston, Massachusetts, USA
    Search for more papers by this author
  • Rebecca L. Zon,

    1. Division of Hematology/Oncology, Stem Cell Transplantation Program, Boston Children's Hospital, Boston, Massachusetts, USA
    2. Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA; Harvard Stem Cell Institute, Cambridge, Massachusetts, USA; Manton Center for Orphan Disease Research, Boston, Massachusetts, USA
    Search for more papers by this author
  • Tan A. Ince,

    1. Department of Pathology, Braman Family Breast Cancer Institute and Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida, USA
    Search for more papers by this author
  • Ellis J. Neufeld,

    1. Division of Hematology/Oncology, Stem Cell Transplantation Program, Boston Children's Hospital, Boston, Massachusetts, USA
    Search for more papers by this author
  • Paul H. Lerou,

    1. Department of Newborn Medicine and Division of Genetics, Brigham and Women's Hospital; Department of Newborn Medicine, Boston Children's Hospital; Harvard Medical School, Boston, Massachusetts, USA
    Search for more papers by this author
  • Mark D. Fleming,

    1. Department of Pathology, Boston Children's Hospital, Boston, Massachusetts, USA
    Search for more papers by this author
  • George Q. Daley,

    Corresponding author
    1. Division of Hematology/Oncology, Stem Cell Transplantation Program, Boston Children's Hospital, Boston, Massachusetts, USA
    2. Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA; Harvard Stem Cell Institute, Cambridge, Massachusetts, USA; Manton Center for Orphan Disease Research, Boston, Massachusetts, USA
    3. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA; Howard Hughes Medical Institute
    • 1 Blackfan Circle, Karp 7, Boston, Massachusetts 02115, USA
    Search for more papers by this author
    • Telephone: 617-919-2013; Fax: 617-730-0222

  • Suneet Agarwal

    Corresponding author
    1. Division of Hematology/Oncology, Stem Cell Transplantation Program, Boston Children's Hospital, Boston, Massachusetts, USA
    2. Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA; Harvard Stem Cell Institute, Cambridge, Massachusetts, USA; Manton Center for Orphan Disease Research, Boston, Massachusetts, USA
    • 3 Blackfan Circle, CLS 3002, Boston, Massachusetts 02115, USA
    Search for more papers by this author
    • Telephone: 617-919-4610; Fax: 617-919-3359


  • Author contributions: A.B.C.C. and K.E.G.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; E.M.M.: conception and design and collection and/or assembly of data; A.B., O.H., J.D.M., R.L.Z., P.H.L., and M.D.F.: collection and/or assembly of data; B.G. and T.A.I.: data analysis and interpretation; J.Z.: collection and/or assembly of data and data analysis and interpretation; E.J.N.: provision of study material or patients; G.Q.D.: conception and design, data analysis and interpretation, and final approval of manuscript; S.A.: conception and design, provision of study material or patients, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript. A.B.C.C. and K.E.G. contributed equally to this article.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    first published online in STEM CELLS EXPRESS February 8, 2013.

Abstract

In congenital mitochondrial DNA (mtDNA) disorders, a mixture of normal and mutated mtDNA (termed heteroplasmy) exists at varying levels in different tissues, which determines the severity and phenotypic expression of disease. Pearson marrow pancreas syndrome (PS) is a congenital bone marrow failure disorder caused by heteroplasmic deletions in mtDNA. The cause of the hematopoietic failure in PS is unknown, and adequate cellular and animal models are lacking. Induced pluripotent stem (iPS) cells are particularly amenable for studying mtDNA disorders, as cytoplasmic genetic material is retained during direct reprogramming. Here, we derive and characterize iPS cells from a patient with PS. Taking advantage of the tendency for heteroplasmy to change with cell passage, we isolated isogenic PS-iPS cells without detectable levels of deleted mtDNA. We found that PS-iPS cells carrying a high burden of deleted mtDNA displayed differences in growth, mitochondrial function, and hematopoietic phenotype when differentiated in vitro, compared to isogenic iPS cells without deleted mtDNA. Our results demonstrate that reprogramming somatic cells from patients with mtDNA disorders can yield pluripotent stem cells with varying burdens of heteroplasmy that might be useful in the study and treatment of mitochondrial diseases. STEM CELLS2013;31:1287–1297

Ancillary