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

Giuliana Di Rocco, Silvia Baldari, Antonietta Gentile, Maurizio Capogrossi, Gabriele Toietta

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

Stem Cell Res Ther 2018 09 26;9(1):250. Epub 2018 Sep 26.

Department of Research, Advanced Diagnostic and Technological Innovation, IRCCS Regina Elena National Cancer Institute, via E. Chianesi 53, 00144, Rome, Italy.

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.

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http://dx.doi.org/10.1186/s13287-018-0986-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158916PMC
September 2018
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References

(Supplied by CrossRef)

G Shefer et al.
Dev Biol 2006

L Heslop et al.
J Cell Sci 2000

D Skuk et al.
Expert Opin Biol Ther 2015

C Loebel et al.
Cell Stem Cell 2018

GT de Souza et al.
Stem Cells Int 2015

NC Chang et al.
Trends Mol Med 2016

HM Blau et al.
Proc Natl Acad Sci U S A 1983

S Decary et al.
Hum Gene Ther 1997

KI Gawlik et al.
Int J Mol Sci 2018

D Skuk et al.
J Neuropathol Exp Neurol 2003

M Bouchentouf et al.
Gene Ther 2008

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