SWI/SNF-Mediated Lineage Determination in Mesenchymal Stem Cells Confers Resistance to Osteoporosis

Kevin Hong Nguyen, Fuhua Xu, Stephen Flowers, Edek A.J. Williams, J. Christopher Fritton, Elizabeth Moran

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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.

Original languageEnglish
Pages (from-to)3028-3038
Number of pages11
JournalStem Cells
Volume33
Issue number10
DOIs
StatePublished - 1 Oct 2015
Externally publishedYes

Keywords

  • Adipocytes
  • Mesenchymal stem cells
  • Osteoblasts
  • Osteoporosis
  • SWI/SNF
  • mammalian brahma, BRM

Fingerprint

Dive into the research topics of 'SWI/SNF-Mediated Lineage Determination in Mesenchymal Stem Cells Confers Resistance to Osteoporosis'. Together they form a unique fingerprint.

Cite this