Journal
TRANSPLANTATION
Volume 97, Issue 3, Pages 273-279Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/01.TP.0000438627.68225.25
Keywords
NPCCs; PGC-1; Dx; Transdifferentiation; Pdx-1
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Funding
- Korea Healthcare Technology R&D Project of the Ministry of Health, Welfare Family Affairs [A092258]
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Background Peroxisome proliferator-activated receptor gamma-coactivator-1 (PGC-1) has recently been implicated as a crucial factor in the glucocorticoid-suppressed expansion and transdifferentiation of porcine neonatal pancreatic cell clusters (NPCCs). However, the molecular mechanism has not been clarified. Methods We investigated whether the suppression of PGC-1 expression protects against -cell dysfunction induced by dexamethasone (Dx) treatment in vitro and in vivo and determined the mechanism of action of PGC-1 in porcine NPCCs. Results The reduction in Pdx-1 gene expression caused by either Dx treatment or PGC-1 overexpression was normalized by siPGC-1. Nuclear FOXO1 and cytoplasmic Pdx-1 were detected after Dx treatment. However, FOXO1 was observed in the cytoplasm, and Pdx-1 was observed in the nucleus after siPGC-1. Suppression of PGC-1 by siPGC-1 improved the Dx-induced repression of insulin secretion and insulin content. In vivo studies showed that the glucose level in the Ad-siPGC-1-infected group was significantly lower than that in the Dx-treated group. Insulin expression in the graft tissue disappeared in the Dx-injected group. However, the siPGC-1- and Dx-treated group showed increased insulin expression and an increase in graft mass, -cell mass, and -cell % in the graft. Conversely, the Dx-induced ductal cystic area was markedly reduced in the siPGC-1- and Dx-treated group. Conclusions Our results suggest that the transdifferentiation of porcine NPCCs into cells is influenced by the duration of the Dx treatment, which might result from the suppression of key pancreatic transcription factors. PGC-1 is an attractive target for modulating the deleterious effects of glucocorticoids on pancreatic stem cells.
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