We conclude that ATM is required to promote expression of SOD2 within the mammary epithelium, and that both ATM and SOD2 play a crucial role in mammary gland homeostasis.
Background: Islet transplantation with neonatal porcine islets (NPIs) is a promising treatment for type 1 diabetes (T1D), but immune rejection poses a major hurdle for clinical use. Innate immune-derived reactive oxygen species (ROS) synthesis can facilitate islet xenograft destruction and enhance adaptive immune responses. Methods: To suppress ROS-mediated xenograft destruction, we utilized nanothin encapsulation materials composed of multilayers of tannic acid (TA), an antioxidant, and a neutral polymer, poly(N-vinylpyrrolidone) (PVPON). We hypothesized that (PVPON/TA)-encapsulated NPIs will maintain euglycemia and dampen proinflammatory innate immune responses following xenotransplantation. Results: (PVPON/TA)-encapsulated NPIs were viable and glucose-responsive similar to non-encapsulated NPIs. Transplantation of (PVPON/TA)-encapsulated NPIs into hyperglycemic C57BL/6.Rag or NOD.Rag mice restored euglycemia, exhibited glucose tolerance, and maintained islet-specific transcription factor levels similar to non-encapsulated NPIs. Gene expression analysis of (PVPON/TA)-encapsulated grafts post-transplantation displayed reduced proinflammatory Ccl5, Cxcl10, Tnf, and Stat1 while enhancing alternatively activated macrophage Retnla, Arg1, and Stat6 mRNA accumulation compared with controls. Flow cytometry analysis demonstrated
Type 1 diabetes is an autoimmune disease characterized by insulin-producing beta-cell destruction. While islet transplantation restores euglycemia and improves patient outcomes, an ideal transplant site remains elusive. Brown adipose tissue (BAT) is a highly vascularized and anti-inflammatory microenvironment. As these tissue features can promote islet graft survival, we hypothesize that islets transplanted into BAT will maintain islet graft and BAT function, while delaying immune-mediated rejection. We performed syngeneic and allogeneic islet transplants into BAT or under the kidney capsule of streptozotocin (STZ)-induced diabetic NOD.Rag and NOD mice to investigate islet graft function, BAT function, metabolism, and immune-mediated rejection. Islet grafts within BAT restored euglycemia similarly to kidney capsule controls. Islets transplanted in BAT maintained expression of islet hormones, transcription factors, and were vascularized.Compared to kidney capsule and euglycemic mock surgery controls, no differences in glucose or insulin tolerance, thermogenic regulation, or energy expenditure were observed with islet grafts in BAT. Immune profiling of BAT revealed enriched antiinflammatory macrophages and T cells. Compared to kidney capsule, islets transplanted in BAT demonstrated significant delays in autoimmune and allograft rejection, possibly due to increased anti-inflammatory immune populations. Our data support BAT as an alternative islet transplantation site that may improve graft survival.
Excess nutrients and proinflammatory cytokines impart stresses on pancreatic islet β-cells that, if unchecked, can lead to cellular dysfunction and/or death. Among these stress-induced effects is loss of key β-cell transcriptional regulator mRNA and protein levels required for β-cell function. Previously, our lab and others reported that LIM-domain complexes comprised the LDB1 transcriptional co-regulator and Islet-1 (ISL1) transcription factor are required for islet β-cell development, maturation, and function. The LDB1:ISL1 complex directly occupies and regulates key β-cell genes, including
MafA, Pdx1
, and
Slc2a2
, to maintain β-cell identity and function. Given the importance of LDB1:ISL1 complexes, we hypothesized that LDB1 and/or ISL1 levels, like other transcriptional regulators, are sensitive to β-cell nutrient and cytokine stresses, likely contributing to β-cell (dys)function under various stimuli. We tested this by treating β-cell lines or primary mouse islets with elevating glucose concentrations, palmitate, or a cytokine cocktail of IL-1β, TNFα, and IFNγ. We indeed observed that LDB1 mRNA and/or protein levels were reduced upon palmitate and cytokine (cocktail or singly) incubation. Conversely, acute high glucose treatment of β-cells did not impair LDB1 or ISL1 levels, but increased LDB1:ISL1 interactions. These observations suggest that LDB1:ISL1 complex formation is sensitive to β-cell stresses and that targeting and/or stabilizing this complex may rescue lost β-cell gene expression to preserve cellular function.
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