Intranuclear Actin Structure Modulates Mesenchymal Stem Cell Differentiation

Buer Sen, Gunes Uzer, Rebekah M. Samsonraj, Zhihui Xie, Cody McGrath, Maya Styner, Amel Dudakovic, Andre J. van Wijnen, Janet Rubin

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Actin structure contributes to physiologic events within the nucleus to control mesenchymal stromal cell (MSC) differentiation. Continuous cytochalasin D (Cyto D) disruption of the MSC actin cytoskeleton leads to osteogenic or adipogenic differentiation, both requiring mass transfer of actin into the nucleus. Cyto D remains extranuclear, thus intranuclear actin polymerization is potentiated by actin transfer: we asked whether actin structure affects differentiation. We show that secondary actin filament branching via the Arp2/3 complex is required for osteogenesis and that preventing actin branching stimulates adipogenesis, as shown by expression profiling of osteogenic and adipogenic biomarkers and unbiased RNA-seq analysis. Mechanistically, Cyto D activates osteoblast master regulators (e.g., Runx2, Sp7, Dlx5) and novel coregulated genes (e.g., Atoh8, Nr4a3, Slfn5). Formin-induced primary actin filament formation is critical for Arp2/3 complex recruitment: osteogenesis is prevented by silencing of the formin mDia1, but not its paralog mDia2. Furthermore, while inhibition of actin, branching is a potent adipogenic stimulus, silencing of either mDia1 or mDia2 blocks adipogenic gene expression. We propose that mDia1, which localizes in the cytoplasm of multipotential MSCs and traffics into the nucleus after cytoskeletal disruption, joins intranuclear mDia2 to facilitate primary filament formation before mediating subsequent branching via Arp2/3 complex recruitment. The resulting intranuclear branched actin network specifies osteogenic differentiation, while actin polymerization in the absence of Arp2/3 complex-mediated secondary branching causes adipogenic differentiation. Stem Cells 2017;35:1624–1635.

Original languageEnglish (US)
Pages (from-to)1624-1635
Number of pages12
JournalStem Cells
Volume35
Issue number6
DOIs
StatePublished - Jun 2017

Keywords

  • Adipocyte
  • Arp2/3 complex
  • Branched actin network
  • CK666
  • Osteoblast
  • mDia1

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

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  • Cite this

    Sen, B., Uzer, G., Samsonraj, R. M., Xie, Z., McGrath, C., Styner, M., Dudakovic, A., van Wijnen, A. J., & Rubin, J. (2017). Intranuclear Actin Structure Modulates Mesenchymal Stem Cell Differentiation. Stem Cells, 35(6), 1624-1635. https://doi.org/10.1002/stem.2617