Re-Expression of IGF-II Is Important for Beta Cell Regeneration in Adult Mice

Abstract

BackgroundThe key factors which support re-expansion of beta cell numbers after injury are largely unknown. Insulin-like growth factor II (IGF-II) plays a critical role in supporting cell division and differentiation during ontogeny but its role in the adult is not known. In this study we investigated the effect of IGF-II on beta cell regeneration.Methodology/Principal FindingsWe employed an in vivo model of ‘switchable’ c-Myc-induced beta cell ablation, pIns-c-MycERTAM, in which 90% of beta cells are lost following 11 days of c-Myc (Myc) activation in vivo. Importantly, such ablation is normally followed by beta cell regeneration once Myc is deactivated, enabling functional studies of beta cell regeneration in vivo. IGF-II was shown to be re-expressed in the adult pancreas of pIns-c-MycERTAM/IGF-II+/+ (MIG) mice, following beta cell injury. As expected in the presence of IGF-II beta cell mass and numbers recover rapidly after ablation. In contrast, in pIns-c-MycERTAM/IGF-II+/− (MIGKO) mice, which express no IGF-II, recovery of beta cell mass and numbers were delayed and impaired. Despite failure of beta cell number increase, MIGKO mice recovered from hyperglycaemia, although this was delayed.Conclusions/SignificanceOur results demonstrate that beta cell regeneration in adult mice depends on re-expression of IGF-II, and supports the utility of using such ablation-recovery models for identifying other potential factors critical for underpinning successful beta cell regeneration in vivo. The potential therapeutic benefits of manipulating the IGF-II signaling systems merit further exploration.

A CCR2+ myeloid cell niche required for pancreatic β cell growth

“…Our gene profiling and functional studies of pancreatic CCR2 + cells further identify this myeloid subset as a prominent source of IGF2 contributing to IGF1R-mediated mitogenic signaling in vivo and in vitro. While consistent with β cell proproliferative effects noted in IGF2-transgenic models (58,59), these findings uncover a paracrine component of the activation of this signaling pathway, which is dependent on CCR2 + myeloid cells trafficking through the pancreas. The negative impact that impairing this pathway has on endocrine cell mass was previously undetected in IGF1R-knockout models, as the analysis focused on adult mice beyond the perinatal stage of β cell expansion, although endocrine dysfunction was noted (60)(61)(62).…”

Early life antibiotic exposure affects pancreatic islet development and metabolic regulation

“…3A ). We also measured mRNA expression of insulin-like growth factor ( IGF)-2 , which is involved in β-cell regeneration and proliferation 39 and has been reported to be maternally imprinted and epigenetically regulated in newborns exposed to antibiotics 40 . Pancreas from ANTI pigs had 1.5-fold higher IGF-2 expression compared to CON at PND 21 ( Fig.…”

Paternal Insulin-like Growth Factor 2 (Igf2) Regulates Stem Cell Activity During Adulthood

“…In adult mice, Igf2 appears to be re-expressed in specific cell types during regeneration (e.g. Alzhanov et al, 2010, Hovey et al, 2003, Zhou et al, 2012). As tissue development, homeostasis and response to injuries are ensured by stem cells that are present in the different tissues, these data suggest that IGF2 is involved in organ maintenance, and raise the question of its role in the biology of adult stem cells.…”