In 2019, Veres et al. contribute to neogenesis . To date, the argument continuesmost recently with the determination of considerable heterogeneity within pancreatic cells, including the ductal populations [79,80,81]. 5.2. SNX-2112 Partial Pancreatectomy: Dedifferentiation/Redifferentiation? Experiments involving partial pancreatectomy (Ppx) in rats showed that in conditions of chronic hyperglycemia, the remaining beta cells downregulate the expression of important beta cell associated genes such as insulin, GLUT2 and glucokinase and upregulate the expression of so-called disallowed genes (i.e., those associated with a non-beta cell fate) in response to this acute stress [82,83,84]. These cells were also shown to have severely impaired insulin secretion in response to glucose activation, which was interpreted to be caused by the dedifferentiation of beta cells to a less mature state. Subsequent studies decided that many of these disallowed genes were also upregulated in the islets of T2D individuals. Although the extent that dedifferentiation contributes to loss of beta cell mass has been more difficult to verify in humans, several single cell RNA-seq studies on T2D islets and the generation of genetic SNX-2112 mutations in mice have identified a number of transcriptional regulators that could contribute to the loss of beta cell functional maturity, including PDX1, FOXO1, and NEUROD1 [11,14,85,86,87,88]. Although additional studies will be necessary to understand the molecular mechanisms associated with the dedifferentiation process, the realization that beta cell dedifferentiation could contribute to the number of beta cells with decreased functionality in T2D suggests it may be possible to develop alternative regenerative therapies focused on the re-differentiation of the beta cell populace. 5.3. Beta Cell Ablation Models: Plasticity? One of the more amazing observations in recent yearsfirst in genetic mouse models and now with some validation in human tissuesis the amazing plasticity of adult endocrine cells. Several mouse genetic models in which pancreatic transcriptional regulators have been deleted have revealed robust transdifferentiation between the alpha and beta cell lineages [89,90,91,92]. There are also now several examples in which islet cells can undergo intercellular conversion upon exposure to stress. In rodent models of severe diabetes (i.e., beta cell ablation), alpha cells became transdifferentiated into functional beta cells ; although their incapacity for proliferation compromised their ability to completely rescue the diabetic state in terms of beta cell number. Interestingly, alpha cells were only able to transdifferentiate early in life, while delta cells were capable of transforming to beta cells later in life . This suggests there may be a temporal windows for certain intra-islet plasticity in the rodent system. van der Meulen et al. have also proposed the Rabbit Polyclonal to B4GALT5 intriguing idea that the immature beta cell populace located within a neogenic niche SNX-2112 may represent an intermediate stage in the transdifferentation of alpha cells to beta cells . Although most examples of interconversion between the islet lineages come from rodent models, there is evidence of beta cells co-expressing insulin and other endocrine hormones in T2D islets, which may represent a transient stage in the transdifferentiation process [95,96]. Again, evidence of islet plasticity raises the exciting possibility of alternative regenerative strategies for restoring functional beta cells in diabetes. 6. Mechanisms of Beta Cell Proliferation Although beta cell replication is usually a rare event, evidence that it can be stimulated in certain conditions raises the hope that this augmentation of beta cell proliferation could be a potential regenerative therapy. Studies of natural and artificial models of beta cell mass growth in rodents have begun to shed light on the molecular mechanisms involved, providing essential knowledge required to translate these findings to utilize proliferation as a therapeutic that promotes human beta cell proliferation. 6.1. Cell Cycle Regulators One obvious area of interest is cell cycle regulators and how they can promote or suppress beta cell replication. In rodents, Georgia and Bhushan exhibited that Cyclin D2 was uniquely required for beta cell replication in the early postnatal period. It was expressed at high levels in beta cells up to two weeks postnatally but was downregulated in adult beta cells . Furthermore, the deletion of Cyclin D2 resulted in the impaired postnatal growth of beta cells. A subsequent study by Kushner et al. exhibited that combined functions of CyclinD1 and D2 were necessary for postnatal beta cell proliferation . This might suggest that reactivating these cyclins would be sufficient to promote beta cell replication in adults; and indeed you will find reports that.
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- We observed that dental administration of NK-4 (1 mg/kg) for 3 days to C57BL/6N mice increased the population of invariant NKT (iNKT) cells that secreted higher levels of IFN- upon activation with -galactosylceramide, when compared to iNKT cells from vehicle-administered mice 
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- Supernatants collected 1 hr after activation with IgE/anti-IgE were used to assess the effect of ramatroban