Abstract
BackgroundCell 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.MethodsWe 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.ResultsWe 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.ConclusionsCollectively, 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.
Highlights
Cell therapy for degenerative diseases aims at rescuing tissue damage by delivery of precursor cells
Protein disulfide isomerase levels are increased in mdx versus wild-type skeletal muscle The mdx mouse is the most common animal model used in Duchenne muscular dystrophy (DMD) research
We revealed that Protein disulfide isomerase (PDI) expression is stronger in mdx regenerating muscle (Fig. 1), suggesting a possible induction of endoplasmic reticulum (ER) stress caused by accumulation of the misfolded truncated form of dystrophin [20]
Summary
Cell therapy for degenerative diseases aims at rescuing tissue damage by delivery of precursor cells. 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. 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. Cell therapy approaches for degenerative muscle diseases aim at. Myoblast transplantation treatment has been generally ineffective given that the functional support of engrafted cells is limited due to massive donor cell death shortly after transplantation [10,11,12]. Direct muscle injection exposes transplanted cells to prolonged periods of hypoxia, exacerbated in dystrophic muscles which are characterized by high levels of reactive oxygen species (ROS) [16]
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