A5053200897- Pancreatic function and diabetes
- Diabetes and associated disorders
- Diabetes Management and Research
- Xenotransplantation and immune response
- Cannabis and Cannabinoid Research
- Pancreatitis Pathology and Treatment
- Pancreatic and Hepatic Oncology Research
- Diabetes Treatment and Management
- Immune Cell Function and Interaction
- Metabolism, Diabetes, and Cancer
- Renal Transplantation Outcomes and Treatments
- Organ Transplantation Techniques and Outcomes
- Genetics and Neurodevelopmental Disorders
- Tissue Engineering and Regenerative Medicine
- Pluripotent Stem Cells Research
- Receptor Mechanisms and Signaling
- Animal Genetics and Reproduction
- Single-cell and spatial transcriptomics
- Virus-based gene therapy research
- Endoplasmic Reticulum Stress and Disease
- Gallbladder and Bile Duct Disorders
- T-cell and B-cell Immunology
- Liver Disease Diagnosis and Treatment
- Diet, Metabolism, and Disease
- Signaling Pathways in Disease
Imagineering (Japan)
2024
Policlinico di Modena
2024
Allegheny Health Network
2014-2023
Allegheny-Singer Research Institute
2015-2023
Weatherford College
2022
Carnegie Mellon University
2018-2022
Nashville Oncology Associates
2018-2022
Ghent University
2022
Cleveland Clinic
2020
University of Pittsburgh
2008-2019
The enzyme α1,3-galactosyltransferase (α1,3GT or GGTA1) synthesizes α1,3-galactose (α1,3Gal) epitopes (Galα1,3Galβ1,4GlcNAc-R), which are the major xenoantigens causing hyperacute rejection in pig-to-human xenotransplantation. Complete removal of α1,3Gal from pig organs is critical step toward success We reported earlier targeted disruption one allele α1,3GT gene cloned pigs. A selection procedure based on a bacterial toxin was used to select for cells second knocked out. Sequencing analysis...
T cells target peptide combos One of the enduring mysteries autoimmunity is identity specific proteins targeted by autoimmune cells. Delong et al. used mass spectrometry to elucidate targets isolated from a mouse model type 1 diabetes. hybrid peptides formed covalent linking derived pro-insulin other found in pancreatic beta islets two individuals with diabetes also recognized such peptides, suggesting that they may play an important role driving disease. Science , this issue p. 711
Proliferation of pancreatic islet beta cells is an important mechanism for self-renewal and adaptive expansion. Increased expression the Ink4a/Arf locus, which encodes cyclin-dependent kinase inhibitor p16(INK4a) tumor suppressor p19(Arf), limits beta-cell regeneration in aging mice, but basis regulation poorly understood. Here we show that Enhancer zeste homolog 2 (Ezh2), a histone methyltransferase component Polycomb group (PcG) protein complex, represses cells. Ezh2 levels decline cells,...
Xenotransplantation of porcine islets into diabetic non-human primates is characterized by (i) an initial massive graft loss possibly due to the instant blood-mediated inflammatory reaction and (ii) requirement intensive, clinically unfriendly immunosuppressive therapy. We investigated whether transgenic expression a human complement-regulatory protein (hCD46) on would improve outcome islet xenotransplantation in streptozotocin-induced Cynomolgus monkeys. Immunosuppression consisted...
Many patients with type 1 diabetes (T1D) have residual β cells producing small amounts of C-peptide long after disease onset but develop an inadequate glucagon response to hypoglycemia following T1D diagnosis. The features these and α in the islet endocrine compartment are largely unknown, due difficulty comprehensive investigation. By studying pancreas isolated islets, we show that remnant appeared maintain several aspects regulated insulin secretion. However, function was markedly reduced,...
Molecular evidence of cellular heterogeneity in the human exocrine pancreas has not been yet established because local concentration and cascade hydrolytic enzymes that can rapidly degrade cells RNA upon pancreatic resection. We sought to better understand composition neonates adults healthy diseased conditions using single-cell sequencing approaches.We innovated single-nucleus RNA-sequencing protocols profiled more than 120,000 from pancreata adult neonatal donors. validated findings...
Enzymatic digestion of donor pancreases is a vital step in human and large mammalian islet isolation. The variable enzymatic activities different batches commercially available collagenase major obstacle achieving reproducibility isolation procedures. In the present work, effectiveness Liberase, standardized mixture highly purified enzymes recently developed for separation islets, was compared with that traditional preparation (type P). results 50 isolations using Liberase enzyme were those...
The process of human islet isolation triggers a cascade stressful events in the islets Langerhans involving activation apoptosis and necrosis production proinflammatory molecules that negatively influence yield function may produce detrimental effects after transplantation. In this study, we showed nuclear factor-kappaB (NF-kappaB) poly(ADP-ribose) polymerase (PARP), two major pathways responsible for cellular responses to stress, already occurs pancreatic cells during procedure....
Early impairment of islet function and graft loss limit the success allogeneic transplantation. Nonspecific inflammatory events occurring at transplant site immediately after grafting, involving production cytokines free radicals sinusoidal endothelial cell (SEC) activation, may contribute to damage. To evaluate whether Kupffer inactivation would result in prolonged allograft survival a model system intrahepatic transplantation rats, we systemically administered either gadolinium chloride...
Successful islet transplantation depends on the infusion of sufficiently large quantities islets, but only a fraction transplanted islets can survive and become engrafted, yet underlying mechanism remains unclear. In this study, we examined effect sirolimus, key component immunosuppressive regimen in clinical transplantation, engraftment function. To distinguish sirolimus immune rejection from its engraftment, used syngeneic model. Diabetic mice were with 250 under renal capsule, followed by...
The generation of pigs with genetic modifications has significantly advanced the field xenotransplantation. New genetically engineered were produced on an α1,3-galactosyltransferase gene-knockout background ubiquitous expression human CD46, islet beta cell-specific tissue factor pathway inhibitor and/or CD39 porcine CTLA4-lg. Isolated islets from 3, 4 or 5 transplanted intraportally into streptozotocin-diabetic, immunosuppressed cynomolgus monkeys (n = 5). Immunosuppression was based...
Pancreatic islet β-cell insufficiency underlies pathogenesis of diabetes mellitus; thus, functional replacement from renewable sources is the focus intensive worldwide effort. However, in vitro production progeny that secrete insulin response to physiological cues primary human cells has proven elusive. Here we describe fractionation, expansion and conversion adult pancreatic ductal into resembling native β-cells. FACS-sorted clonally expanded as spheres culture, while retaining...
Cystic fibrosis-related (CF-related) diabetes (CFRD) is an increasingly common and devastating comorbidity of CF, affecting approximately 35% adults with CF. However, the underlying causes CFRD are unclear. Here, we examined cystic fibrosis transmembrane conductance regulator (CFTR) islet expression whether CFTR participates in endocrine cell function using murine models β deletion normal CF human pancreas islets. Specific from cells did not affect function. In islets, mRNA was minimally...
Inadequate pancreatic β cell function underlies type 1 and 2 diabetes mellitus. Strategies to expand functional cells have focused on discovering controlling mechanisms that limit the proliferation of human cells. Here, we developed an engraftment strategy examine age-associated islet replication competence reveal underlying age-dependent decline in islets. We found exendin-4 (Ex-4), agonist glucagon-like peptide receptor (GLP-1R), stimulates juvenile but not adult This responsiveness does...
Type 1 diabetes studies consistently generate data showing islet β-cell dysfunction and T cell–mediated anti-β-cell–specific autoimmunity. To explore the pathogenesis, we interrogated transcriptomes from donors with without type using both bulk-sorted single β-cells. Consistent immunohistological studies, β-cells displayed increased Class I transcripts associated mRNA species. These also expressed for II antigen presentation pathway components, but lacked macrophage marker CD68....