Downregulation of thymosin β4 in neural progenitor grafts promotes spinal cord regeneration

Cristiana Mollinari, Lucia Ricci-Vitiani, Massimo Pieri, Corrado Lucantoni, Anna Maria Rinaldi, Mauro Racaniello, Ruggero De Maria, Cristina Zona, Roberto Pallini, Daniela Merlo, Enrico Garaci

Research output: Contribution to journalArticlepeer-review

Abstract

Thymosin β4 (Tβ4) is an actin-binding peptide whose expression in developing brain correlates with migration and neurite extension of neurons. Here, we studied the effects of the downregulation of Tβ4 expression on growth and differentiation of murine neural progenitor cells (NPCs), using an antisense lentiviral vector. In differentiation-promoting medium, we found twice the number of neurons derived from the Tβ4-antisense-transduced NPCs, which showed enhanced neurite outgrowth accompanied by increased expression of the adhesion complex N-cadherin-β-catenin and increased ERK activation. Importantly, when the Tβ4-antisense-transduced NPCs were transplanted in vivo into a mouse model of spinal cord injury, they promoted a significantly greater functional recovery. Locomotory recovery correlated with increased expression of the regeneration-promoting cell adhesion molecule L1 by the grafted Tβ4-antisense-transduced NPCs. This resulted in an increased number of regenerating axons and in sprouting of serotonergic fibers surrounding and contacting the Tβ4-antisense-transduced NPCs grafted into the lesion site. In conclusion, our data identify a new role for Tβ4 in neuronal differentiation of NPCs by regulating fate determination and process outgrowth. Moreover, NPCs with reduced Tβ4 levels generate an L1-enriched environment in the lesioned spinal cord that favors growth and sprouting of spared host axons and enhances the endogenous tissue-repair processes.

Original languageEnglish
Pages (from-to)4195-4207
Number of pages13
JournalJournal of Cell Science
Volume122
Issue number22
DOIs
Publication statusPublished - Nov 15 2009

Keywords

  • Adhesion molecules
  • Neural progenitor cell graft
  • Neurite outgrowth
  • Neuronal differentiation
  • Spinal cord injury
  • Thymosin β4

ASJC Scopus subject areas

  • Cell Biology

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