title: Bone marrow skeletal stem/progenitor cell defects in dyskeratosis congenita and telomere biology disorders.
abstract: Dyskeratosis congenita (DC) is an inherited multisystem disorder, characterized by oral leukoplakia, nail dystrophy, and abnormal skin pigmentation, as well as high rates of bone marrow (BM) failure, solid tumors, and other medical problems such as osteopenia. DC and telomere biology disorders (collectively referred to as TBD here) are caused by germline mutations in telomere biology genes leading to very short telomeres and limited proliferative potential of hematopoietic stem cells. We found that skeletal stem cells (SSCs) within the BM stromal cell population (BMSCs, also known as BM-derived mesenchymal stem cells), may contribute to the hematologic phenotype. TBD-BMSCs exhibited reduced clonogenicity, spontaneous differentiation into adipocytes and fibrotic cells, and increased senescence in vitro. Upon in vivo transplantation into mice, TBD-BMSCs failed to form bone or support hematopoiesis, unlike normal BMSCs. TERC reduction (a TBD-associated gene) in normal BMSCs by small interfering TERC-RNA (siTERC-RNA) recapitulated the TBD-BMSC phenotype by reducing proliferation and secondary colony-forming efficiency, and by accelerating senescence in vitro. Microarray profiles of control and siTERC-BMSCs showed decreased hematopoietic factors at the messenger RNA level and decreased secretion of factors at the protein level. These findings are consistent with defects in SSCs/BMSCs contributing to BM failure in TBD.
authors.affiliation: Skeletal Biology Section, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research.
authors.forename: Arun
authors.initials: A
authors.lastname: Balakumaran
authors.affiliation: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, and.
authors.forename: Prasun J
authors.initials: PJ
authors.lastname: Mishra
authors.affiliation: Laboratory of Diagnostic Radiology Research, Warren G. Magnuson Clinical Center, National Institutes of Health, Department of Health and Human Services, Bethesda, MD;
authors.forename: Edyta
authors.initials: E
authors.lastname: Pawelczyk
authors.affiliation: Skeletal Biology Section, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research.
authors.forename: Sayuri
authors.identifier: http://orcid.org/0000-0002-0976-8521
authors.initials: S
authors.lastname: Yoshizawa
authors.affiliation: Skeletal Biology Section, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Sworder
authors.affiliation: Skeletal Biology Section, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research.
authors.forename: Natasha
authors.initials: N
authors.lastname: Cherman
authors.affiliation: Skeletal Biology Section, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research.
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Kuznetsov
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy; and.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bianco
authors.affiliation: Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute and.
authors.forename: Neelam
authors.initials: N
authors.lastname: Giri
authors.affiliation: Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute and.
authors.forename: Sharon A
authors.identifier: http://orcid.org/0000-0001-6006-0740
authors.initials: SA
authors.lastname: Savage
authors.affiliation: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, and.
authors.forename: Glenn
authors.initials: G
authors.lastname: Merlino
authors.affiliation: Hematology Branch, National Heart Lung and Blood Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Dumitriu
authors.affiliation: Hematology Branch, National Heart Lung and Blood Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD.
authors.forename: Cynthia E
authors.initials: CE
authors.lastname: Dunbar
authors.affiliation: Hematology Branch, National Heart Lung and Blood Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD.
authors.forename: Neal S
authors.initials: NS
authors.lastname: Young
authors.affiliation: Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute and.
authors.forename: Blanche P
authors.initials: BP
authors.lastname: Alter
authors.affiliation: Skeletal Biology Section, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research.
authors.forename: Pamela G
authors.initials: PG
authors.lastname: Robey
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D049109:Cell Proliferation; D016922:Cellular Senescence; D002648:Child; D002675:Child, Preschool; D003114:Colony-Forming Units Assay; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D019871:Dyskeratosis Congenita / Q000235:genetics* / Q000473:pathology; D005260:Female; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D012313:RNA / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016615:Telomere / Q000737:chemistry / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; C440868:TINF2 protein, human; D034501:Telomere-Binding Proteins; C422952:telomerase RNA; D012313:RNA; C509186:TERT protein, human; D019098:Telomerase; C532890:RTEL1 protein, human; D004265:DNA Helicases