title: SWI/SNF-Mediated Lineage Determination in Mesenchymal Stem Cells Confers Resistance to Osteoporosis.
abstract: Redirecting the adipogenic potential of bone marrow-derived mesenchymal stem cells to other lineages, particularly osteoblasts, is a key goal in regenerative medicine. Controlling lineage selection through chromatin remodeling complexes such as SWI/SNF, which act coordinately to establish new patterns of gene expression, would be a desirable intervention point, but the requirement for the complex in essentially every lineage pathway has generally precluded selectivity. However, a novel approach now appears possible by targeting the subset of SWI/SNF powered by the alternative ATPase, mammalian brahma (BRM). BRM is not required for development, which has hindered understanding of its contributions, but knockdown genetics here, designed to explore the hypothesis that BRM-SWI/SNF has different regulatory roles in different mesenchymal stem cell lineages, shows that depleting BRM from mesenchymal stem cells has a dramatic effect on the balance of lineage selection between osteoblasts and adipocytes. BRM depletion enhances the proportion of cells expressing markers of osteoblast precursors at the expense of cells able to differentiate along the adipocyte lineage. This effect is evident in primary bone marrow stromal cells as well as in established cell culture models. The altered precursor balance has major physiological significance, which becomes apparent as protection against age-related osteoporosis and as reduced bone marrow adiposity in adult BRM-null mice.
authors.affiliation: Department of Orthopaedics, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA.
authors.forename: Kevin Hong
authors.initials: KH
authors.lastname: Nguyen
authors.affiliation: Department of Orthopaedics, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA.
authors.forename: Fuhua
authors.initials: F
authors.lastname: Xu
authors.affiliation: Department of Orthopaedics, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Flowers
authors.affiliation: Department of Orthopaedics, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA.
authors.forename: Edek A J
authors.initials: EA
authors.lastname: Williams
authors.affiliation: Department of Orthopaedics, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA.
authors.forename: J Christopher
authors.initials: JC
authors.lastname: Fritton
authors.affiliation: Department of Orthopaedics, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Moran
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism; D010024:Osteoporosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D044968:Regenerative Medicine; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C445179:SWI-SNF-B chromatin-remodeling complex; C499503:Smarca2 protein, mouse; D014157:Transcription Factors; D000251:Adenosine Triphosphatases; D004265:DNA Helicases
keywords: Adipocytes; Mesenchymal stem cells; Osteoblasts; Osteoporosis; SWI/SNF; mammalian brahma, BRM