Behan-Bush, R. M. | Search bioRxiv

bioRxiv2025

Proinflammatory cytokines mediate pancreatic beta-cell specific alterations to Golgi morphology via iNOS-dependent mitochondrial inhibition

Type 1 diabetes (T1D) is caused by the selective autoimmune ablation of pancreatic {beta}-cells. Emerging evidence reveals {beta}-cell secretory dysfunction arises early in T1D development and may contribute to diseases etiology; however, the underlying mechanisms are not well understood. Our data reveal that proinflammatory cytokines elicit a complex change in the {beta}-cells Golgi structure and function. The structural modifications include Golgi compaction and loss of the inter-connecting ribbon resulting in Golgi fragmentation. Our data demonstrate that iNOS generated nitric oxide (NO) is necessary and sufficient for {beta}-cell Golgi re-structuring. Moreover, the unique sensitivity of the {beta}-cell to NO-dependent mitochondrial inhibition results in {beta}-cell specific Golgi alterations that are absent in other cell types, including -cells. Collectively, our studies provide critical clues as to how {beta}-cell secretory functions are specifically impacted by cytokines and NO that may contribute to the development of {beta}-cell autoantigens relevant to T1D.

cell biology↗

bioRxiv2022

Toxicity impacts on human adipose MSCs acutely exposed to Aroclor and non-Aroclor mixtures of PCBs.

PCBs accumulate in adipose where they may impact the growth and function of cells within the tissue. This is particularly concerning during adolescence when adipocytes expand rapidly. Herein we sought to understand how exposure to PCB mixtures found in U.S. schools affects human adipose mesenchymal stem/stromal cell (MSC) health and function. We investigated how exposure to Aroclor 1016 and Aroclor 1254, as well as a newly characterized non-Aroclor mixture that resembles the PCB profile found in cabinets, Cabinet Mixture, affects adipose MSC growth, viability, and function in vitro. We found that exposure to all three mixtures resulted in two distinct types of toxicity. At PCB concentrations >20 M, the majority of MSCs die, while at 1-10 M MSCs remained viable but display numerous alterations to their phenotype. At these sublethal concentrations, MSC rate of expansion slowed, and morphology changed. Further assessment revealed PCB-exposed MSCs had impaired adipogenesis and a modest decrease in immunosuppressive capabilities. Thus, exposure to PCB mixtures found in schools negatively impacts the health and function of adipose MSCs. This work has implications for human health due to MSCs role in supporting the growth and maintenance of adipose tissue. SYNOPSISPCB mixtures found in schools are toxic to human adipose mesenchymal stem/stromal cells, stunting their growth and altering their function in ways that could contribute to metabolic diseases.

pharmacology and toxicology↗