Protein disulfide isomerase as a prosurvival factor in cell therapy for muscular and vascular diseases

G. Di Rocco, S. Baldari, A. Gentile, M. Capogrossi, G. Toietta

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: Cell therapy for degenerative diseases aims at rescuing tissue damage by delivery of precursor cells. Thus far, this strategy has been mostly unsuccessful due to massive loss of donor cells shortly after transplantation. Several strategies have been applied to increase transplanted cell survival but only with limited success. The endoplasmic reticulum (ER) is an organelle involved in protein folding, calcium homeostasis, and lipid biosynthesis. Protein disulfide isomerase (PDI) is a molecular chaperone induced and activated by ER stress. PDI is induced by hypoxia in neuronal, cardiac, and endothelial cells, supporting increased cell survival to hypoxic stress and protection from apoptosis in response to ischemia. METHODS: We achieved ex vivo PDI gene transfer into luciferase-expressing myoblasts and endothelial cells. We assessed cell engraftment upon intramuscular transplantation into a mouse model of Duchenne muscular dystrophy (mdx mouse) and into a mouse model of ischemic disease. RESULTS: We observed that loss of full-length dystrophin expression in mdx mice muscle leads to an increase of PDI expression, possibly in response to augmented ER protein folding load. Moreover, we determined that overexpression of PDI confers a survival advantage for muscle cells in vitro and in vivo to human myoblasts injected into murine dystrophic muscle and to endothelial cells administered upon hindlimb ischemia damage, improving the therapeutic outcome of the cell therapy treatment. CONCLUSIONS: Collectively, these results suggest that overexpression of PDI may protect transplanted cells from hypoxia and other possibly occurring ER stresses, and consequently enhance their regenerative properties.
Original languageEnglish
Pages (from-to)250-018-0986-y
JournalStem Cell Research and Therapy
Volume9
Issue number1
DOIs
Publication statusPublished - Oct 1 2018

Keywords

  • Cell and tissue-based therapy
  • Cell survival
  • Duchenne muscular dystrophy
  • Endoplasmic reticulum stress
  • Endothelial cells
  • Ischemia
  • Molecular chaperones
  • Myoblasts
  • Protein disulfide isomerase
  • Regenerative medicine

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