Intranuclear Actin Regulates Osteogenesis

Stem Cells. 2015 Oct;33(10):3065-76. doi: 10.1002/stem.2090.

Abstract

Depolymerization of the actin cytoskeleton induces nuclear trafficking of regulatory proteins and global effects on gene transcription. We here show that in mesenchymal stem cells (MSCs), cytochalasin D treatment causes rapid cofilin-/importin-9-dependent transfer of G-actin into the nucleus. The continued presence of intranuclear actin, which forms rod-like structures that stain with phalloidin, is associated with induction of robust expression of the osteogenic genes osterix and osteocalcin in a Runx2-dependent manner, and leads to acquisition of osteogenic phenotype. Adipogenic differentiation also occurs, but to a lesser degree. Intranuclear actin leads to nuclear export of Yes-associated protein (YAP); maintenance of nuclear YAP inhibits Runx2 initiation of osteogenesis. Injection of cytochalasin into the tibial marrow space of live mice results in abundant bone formation within the space of 1 week. In sum, increased intranuclear actin forces MSC into osteogenic lineage through controlling Runx2 activity; this process may be useful for clinical objectives of forming bone.

Keywords: Bone; Cofilin; Cytoskeleton; Importin 9; Mesenchymal stem cells; Runx2; Yes-associated protein.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actin Cytoskeleton / genetics
  • Actin Cytoskeleton / metabolism*
  • Actin Depolymerizing Factors / metabolism
  • Actins / metabolism*
  • Animals
  • Cell Lineage / genetics
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism
  • Core Binding Factor Alpha 1 Subunit / genetics*
  • Core Binding Factor Alpha 1 Subunit / metabolism
  • Cytochalasin D / administration & dosage
  • Mesenchymal Stem Cells / metabolism*
  • Mice
  • Osteogenesis / genetics*
  • Phalloidine / metabolism
  • Protein Transport / genetics

Substances

  • Actin Depolymerizing Factors
  • Actins
  • Core Binding Factor Alpha 1 Subunit
  • Runx2 protein, mouse
  • Phalloidine
  • Cytochalasin D