title: Impaired function of bone marrow stromal cells in systemic mastocytosis.
abstract: Patients with systemic mastocytosis (SM) have a wide variety of problems, including skeletal abnormalities. The disease results from a mutation of the stem cell receptor (c-kit) in mast cells and we wondered if the function of bone marrow stromal cells (BMSCs; also known as MSCs or mesenchymal stem cells) might be affected by the invasion of bone marrow by mutant mast cells. As expected, BMSCs from SM patients do not have a mutation in c-kit, but they proliferate poorly. In addition, while osteogenic differentiation of the BMSCs seems to be deficient, their adipogenic potential appears to be increased. Since the hematopoietic supportive abilities of BMSCs are also important, we also studied the engraftment in NSG mice of human CD34(+) hematopoietic progenitors, after being co-cultured with BMSCs of healthy volunteers vs. BMSCs derived from patients with SM. BMSCs derived from the bone marrow of patients with SM could not support hematopoiesis to the extent that healthy BMSCs do. Finally, we performed an expression analysis and found significant differences between healthy and SM derived BMSCs in the expression of genes with a variety of functions, including the WNT signaling, ossification, and bone remodeling. We suggest that some of the symptoms associated with SM might be driven by epigenetic changes in BMSCs caused by dysfunctional mast cells in the bone marrow of the patients.
authors.affiliation: Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA. Electronic address: nemethk@mail.nih.gov.
authors.forename: Krisztian
authors.initials: K
authors.lastname: Nemeth
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Wilson
authors.affiliation: Department of Transfusion Medicine, Clinical Center, National Institutes of Health, 10 Center Dr., Bethesda, MD 20892, USA.
authors.forename: Jiaqiang J
authors.initials: JJ
authors.lastname: Ren
authors.affiliation: Department of Transfusion Medicine, Clinical Center, National Institutes of Health, 10 Center Dr., Bethesda, MD 20892, USA.
authors.forename: Marianna
authors.initials: M
authors.lastname: Sabatino
authors.affiliation: Department of Transfusion Medicine, Clinical Center, National Institutes of Health, 10 Center Dr., Bethesda, MD 20892, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Stroncek
authors.affiliation: Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: Miklos
authors.initials: M
authors.lastname: Krepuska
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: Pamela G
authors.initials: PG
authors.lastname: Robey
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: Dean D
authors.initials: DD
authors.lastname: Metcalfe
authors.affiliation: Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA. Electronic address: mezeye@mail.nih.gov.
authors.forename: Eva
authors.initials: E
authors.lastname: Mezey
mesh_terms: D050156:Adipogenesis / Q000235:genetics; D000328:Adult; D000368:Aged; D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology*; D016022:Case-Control Studies; D049109:Cell Proliferation; D048430:Cell Shape; D003114:Colony-Forming Units Assay; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D008297:Male; D034721:Mastocytosis, Systemic / Q000473:pathology*; D051379:Mice; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010012:Osteogenesis / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D017154:Stromal Cells / Q000473:pathology; D014019:Tissue Donors
chemical_list: D019009:Proto-Oncogene Proteins c-kit