Interleukin-10 delivery via mesenchymal stem cells: A novel gene therapy approach to prevent lung ischemia-reperfusion injury

Eddie Manning, Si Pham, Sen Li, Roberto I. Vazquez-Padron, James Mathew, Phillip Ruiz, Shashikumar K. Salgar

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

Ischemia-reperfusion (IR) injury is an important cause of primary graft failure in lung transplantation. In this study, viral interleukin-10 (vIL-10)-engineered mesenchymal stem cells (MSCs) were tested for their ability to prevent lung IR injury. Bone marrow-derived MSCs were transduced with rvIL-10-retrovirus. After 120min of warm left lung ischemia, rats received ∼15×106 vIL-10-engineered MSCs (MSC-vIL-10), empty vector-engineered MSCs (MSC-vec), or saline intravenously. Mean blood oxygenation (PaO2/FiO2 ratio, mmHg) was measured at 4hr, 24hr, 72hr, and 7 days. As early as 4hr post-IR injury with MSC-vIL-10 treatment, blood oxygenation was significantly (p<0.05) improved (319±94; n=7) compared with untreated (saline) controls (63±19; n=6). At 24hr post-IR injury, in the MSC-vIL-10-treated group there was a further increase in blood oxygenation (353±105; n=10) compared with the MSC-vec group (138±86; n=9) and saline group (87±39; n=10). By 72hr, oxygenation reached normal (475±55; n=9) in the MSC-vIL-10-treated group but not in the saline-treated and MSC-vec-treated groups. At 4hr after IR injury, lungs with MSC-vIL10 treatment had a lower (p<0.05) injury score (0.9±0.4) compared with lungs of the untreated (saline) group (2.5±1.4) or MSC-vec-treated group (2±0.4). Lung microvascular permeability and wet-to-dry weight ratios were markedly lower in the MSC-vIL10 group compared with untreated (saline) controls. ISOL (in situ oligonucleotide ligation for DNA fragmentation detection) and caspase-3 staining demonstrated significantly (p<0.05) fewer apoptotic cells in MSC-vIL10-treated lungs. Animals that received MSC-vIL10 therapy had fewer (p<0.05) CD4+ and CD8+ T cells in bronchoalveolar lavage fluid compared with untreated control animals. A therapeutic strategy using vIL-10-engineered MSCs to prevent IR injury in lung transplantation seems promising.

Original languageEnglish (US)
Pages (from-to)713-727
Number of pages15
JournalHuman gene therapy
Volume21
Issue number6
DOIs
StatePublished - Jun 1 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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