Identification of Three Early Phases of Cell-Fate Determination during Osteogenic and Adipogenic Differentiation by Transcription Factor Dynamics

Jeroen van de Peppel, Tanja Strini, Julia Tilburg, Hans Westerhoff, Andre J. van Wijnen, Johannes P. van Leeuwen

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Age-related skeletal degeneration in patients with osteoporosis is characterized by decreased bone mass and occurs concomitant with an increase in bone marrow adipocytes. Using microarray expression profiling with high temporal resolution, we identified gene regulatory events in early stages of osteogenic and adipogenic lineage commitment of human mesenchymal stromal cells (hMSCs). Data analysis revealed three distinct phases when cells adopt a committed expression phenotype: initiation of differentiation (0–3 hr, phase I), lineage acquisition (6–24 hr, phase II), and early lineage progression (48–96 hr, phase III). Upstream regulator analysis identified 34 transcription factors (TFs) in phase I with a role in hMSC differentiation. Interestingly, expression levels of identified TFs did not always change and indicate additional post-transcriptional regulatory mechanisms. Functional analysis revealed that forced expression of IRF2 enhances osteogenic differentiation. Thus, IRF2 and other early-responder TFs may control osteogenic cell fate of MSCs and should be considered in mechanistic models that clarify bone-anabolic changes during clinical progression of osteoporosis.

Original languageEnglish (US)
Pages (from-to)947-960
Number of pages14
JournalStem Cell Reports
Volume8
Issue number4
DOIs
StatePublished - Apr 11 2017

Keywords

  • adipocyte
  • bioinformatics
  • bone
  • gene expression profiling
  • human MSC differentiation
  • interferon
  • osteoblast
  • regenerative medicine
  • transcription factor

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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