Nitric oxide determines mesodermic differentiation of mouse embryonic stem cells by activating class IIa histone deacetylases: Potential therapeutic implications in a mouse model of hindlimb ischemia

Francesco Spallotta, Jessica Rosati, Stefania Straino, Simona Nanni, Annalisa Grasselli, Valeria Ambrosino, Dante Rotili, Sergio Valente, Antonella Farsetti, Antonello Mai, Maurizio C. Capogrossi, Carlo Gaetano, Barbara Illi

Research output: Contribution to journalArticle

Abstract

In human endothelial cells, nitric oxide (NO) results in class IIa histone deacetylases (HDACs) activation and marked histone deacetylation. It is unknown whether similar epigenetic events occur in embryonic stem cells (ESC) exposed to NO and how this treatment could influence ESC therapeutic potential during tissue regeneration. This study reports that the NO-dependent class IIa HDACs subcellular localization and activity decreases the global acetylation level of H3 histones in ESC and that this phenomenon is associated with the inhibition of Oct4, Nanog, and KLF4 expression. Further, a NO-induced formation of macromolecular complexes including HDAC3, 4, 7, and protein phosphatase 2A (PP2A) have been detected. These processes correlated with the expression of the mesodermalspecific protein brachyury (Bry) and the appearance of several vascular and skeletal muscle differentiation markers. These events were abolished by the class IIa-specific inhibitor MC1568 and by HDAC4 or HDAC7 short interfering RNA (siRNA). The ability of NO to induce mesodermic/ cardiovascular gene expression prompted us to evaluate the regenerative potential of these cells in a mouse model of hindlimb ischemia. We found that NO-treated ESCs injected into the cardiac left ventricle selectively localized in the ischemic hindlimb and contributed to the regeneration of muscular and vascular structures. These findings establish a key role for NO and class IIa HDACs modulation in ESC mesodermal commitment and enhanced regenerative potential in vivo.

Original languageEnglish
Pages (from-to)431-442
Number of pages12
JournalStem Cells
Volume28
Issue number3
DOIs
Publication statusPublished - Mar 31 2010

Keywords

  • Chromatin
  • Differentiation
  • Histone deacetylases
  • Nitric oxide
  • Stem cells

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine

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    Spallotta, F., Rosati, J., Straino, S., Nanni, S., Grasselli, A., Ambrosino, V., Rotili, D., Valente, S., Farsetti, A., Mai, A., Capogrossi, M. C., Gaetano, C., & Illi, B. (2010). Nitric oxide determines mesodermic differentiation of mouse embryonic stem cells by activating class IIa histone deacetylases: Potential therapeutic implications in a mouse model of hindlimb ischemia. Stem Cells, 28(3), 431-442. https://doi.org/10.1002/stem.300