Lentiviral vector gene transfer is limited by the proteasome at postentry steps in various types of stem cells

Francesca Romana Santoni De Sio, Angela Gritti, Paolo Cascio, Margherita Neri, Maurilio Sampaolesi, Cesare Galli, Jeremy Luban, Luigi Naldini

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

The isolation of human embryonic and somatic stem cells of different types has made it possible to design novel gene and cell replacement therapies. Vectors derived from retro/lentiviruses are used to stably introduce genes into stem cells and their progeny. However, the permissivity to retroviral infection varies among cell types. We previously showed that hematopoietic stem cells are poorly permissive to human immunodeficiency virus (HIV)-derived vectors and that pharmacological inhibition of the proteasome strongly enhances gene transfer. Here we report that the proteasome limits lentiviral gene transfer in all stem cell types tested, including embryonic, mesenchymal, and neural, of both human and mouse origin. Remarkably, this inhibitory activity was sharply reduced upon differentiation of the stem cells, suggesting that it represents a novel feature of the stem cell/immature progenitor phenotype. Proteasome-mediated inhibition was specific for lentiviral vectors and occurred at a postentry infection step. It was not mediated by activation of nuclear factor-κB, a major signaling pathway modulated by the proteasome, and did not correlate with high proteasome activity. Interaction of the virion core with cyclophilin A was required to maximize the effect of proteasome inhibitor on the infection pathway. These findings are relevant to uncover new mediators of HIV gene transfer and help in designing more effective protocols for the genetic modification of stem cells.

Original languageEnglish
Pages (from-to)2142-2152
Number of pages11
JournalStem Cells
Volume26
Issue number8
DOIs
Publication statusPublished - Aug 2008

Fingerprint

Proteasome Endopeptidase Complex
Stem Cells
Genes
Infection
Cyclophilin A
HIV
Lentivirus
Adult Stem Cells
Proteasome Inhibitors
Cell- and Tissue-Based Therapy
Hematopoietic Stem Cells
Virion
Pharmacology
Phenotype

Keywords

  • Embryonic stem cells
  • Gene transfer
  • Lentiviral vectors
  • Proteasome
  • Proteasome inhibitor
  • Somatic stem cells

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine

Cite this

Lentiviral vector gene transfer is limited by the proteasome at postentry steps in various types of stem cells. / De Sio, Francesca Romana Santoni; Gritti, Angela; Cascio, Paolo; Neri, Margherita; Sampaolesi, Maurilio; Galli, Cesare; Luban, Jeremy; Naldini, Luigi.

In: Stem Cells, Vol. 26, No. 8, 08.2008, p. 2142-2152.

Research output: Contribution to journalArticle

De Sio, Francesca Romana Santoni ; Gritti, Angela ; Cascio, Paolo ; Neri, Margherita ; Sampaolesi, Maurilio ; Galli, Cesare ; Luban, Jeremy ; Naldini, Luigi. / Lentiviral vector gene transfer is limited by the proteasome at postentry steps in various types of stem cells. In: Stem Cells. 2008 ; Vol. 26, No. 8. pp. 2142-2152.
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