Biology subjects

Phelps, E. A.

Publications and source records attributed to Phelps, E. A..

4 recordsLinked to original sources

bioRxiv2023

Serum from pregnant donors induces human beta cell proliferation and insulin secretion

Pancreatic beta cells are among the slowest replicating cells in the human body. Human beta cells usually do not increase in number with exceptions being during the neonatal period, in cases of obesity, and during pregnancy. This project explored maternal serum for stimulatory potential on human beta cell proliferation and insulin output. Gravid, full-term women who were scheduled to undergo cesarean delivery were recruited for this study. A human beta cell line was cultured in media supplemented with serum from pregnant and non-pregnant donors and assessed for differences in proliferation and insulin secretion. A subset of pregnant donor sera induced significant increases in beta cell proliferation and insulin secretion. Pooled serum from pregnant donors also increased proliferation in primary human beta cells but not primary human hepatocytes indicating a cell-type specific effect. This study suggests stimulatory factors in human serum during pregnancy could provide a novel approach for human beta cell expansion.

cell biology↗

bioRxiv2022

Immune engineered extracellular vesicles to modulate T cell activation in the context of type 1 diabetes

Extracellular vesicles (EVs) are small, biologically active, cell-secreted vesicles that can affect immune responses through antigen presentation and co-stimulation or co-inhibition. We generated designer EVs to modulate autoreactive T cells in the context of type 1 diabetes by engineering K562 cells to express HLA-A*02 (HLA-A2) alongside co-stimulatory CD80 and/or co-inhibitory PD-L1. EVs presenting HLA-A2 and CD80 activated CD8+ T cells in a dose, antigen, and HLA-specific manner. Adding PD-L1 to these EVs produced an immunoregulatory response, reducing CD8+ T cell activation and cytotoxicity in vitro. EVs alone could not stimulate T cells without antigen presenting cells (APCs), suggesting that EVs act by cross-dressing APCs. EVs lacking CD80 were ineffective at modulating CD8+ T cell activation, suggesting that both peptide-HLA complex and costimulatory molecules are required for EV-mediated immune modulation through APC cross-dressing. These results provide mechanistic insight into the rational design of EVs as a cell-free, yet precision medicine-based approach to immunotherapy that can be tailored to promote antigen-specific immune tolerance or pro-inflammatory responses.

bioengineering↗

bioRxiv2022

Human threat learning is associated with gut microbiota composition

Rodent studies have shown that the gut microbiota can influence threat and safety learning, which has been linked to anxiety phenotypes. In humans, it has been demonstrated that microbiota composition varies with anxiety disorders, but evidence showing an association with threat learning is lacking. Here, we tested whether individual variability in threat and safety learning was related to gut microbiota composition in healthy adults. We found that threat, but not safety learning varies with individuals microbiome composition. Our results provide evidence that the gut microbiota is associated with excitatory threat learning across species. Significance StatementLearning from threats and safety is a core mechanism of anxiety disorders, and studies in rodent models have shown that the gut microbiota can modulate such behaviors. Although previous literature on humans shows a relationship between emotional circuits and gut microbiota, the evidence linking learning and microbiota is lacking. In a Pavlovian threat conditioning paradigm, we show that patterns of gut microbiota composition in healthy humans relate to their patterns of threat learning, but not safety learning. Our findings suggest one mechanism by which the human gut microbiota is associated with anxiety-related behaviors.

animal behavior and cognition↗

bioRxiv2022

Neuronal growth regulator 1 (NEGR1) promotes synaptic targeting of glutamic acid decarboxylase 65 (GAD65)

Neuronal growth regulator 1 (NEGR1) is a glycosylphosphatidylinositol-anchored cell adhesion molecule encoded by an obesity susceptibility gene. We demonstrate that NEGR1 accumulates in GABAergic inhibitory synapses in hypothalamic neurons, a GABA-synthesizing enzyme GAD65 attaches to the plasma membrane, and NEGR1 promotes clustering of GAD65 at the synaptic plasma membrane. GAD65 is removed from the plasma membrane with newly formed vesicles. The association of GAD65 with vesicles results in increased GABA synthesis. In NEGR1 deficient mice, the synaptic targeting of GAD65 is decreased, the GABAergic synapse densities are reduced, and the reinforcing effects of food rewards are blunted. In mice fed a high fat diet, levels of NEGR1 are increased and GAD65 abnormally accumulates at the synaptic plasma membrane. Our results indicate that NEGR1 regulates a previously unknown step required for synaptic targeting and functioning of GAD65, which can be affected by bidirectional changes in NEGR1 levels causing disruptions in the GABAergic signaling controlling feeding behavior.

neuroscience↗