Advances in Engineering Myeloid Cells for Cell Therapy Applications.

Myeloid cells, including macrophages, neutrophils, dendritic cells, and myeloid-derived suppressor cells, play crucial roles in the innate immune system, contributing to immune defense, tissue homeostasis, and organ development. They have tremendous potential as therapeutic tools for diseases such as cancer and autoimmune disorders, but harnessing cell engineering strategies to enhance potency and expand applications is challenging. Recent advancements in stem cell research have made it possible to differentiate human embryonic stem cells and induce pluripotent stem cells into various cell types, including myeloid cells, offering a promising new approach to generate myeloid cells for cell therapy.

An INSULIN and IAPP dual reporter enables tracking of functional maturation of stem cell-derived insulin producing cells.

Objective: Human embryonic stem cell (hESC; SC)-derived pancreatic β cells can be used to study diabetes pathologies and develop cell replacement therapies. Although current differentiation protocols yield SCβ cells with varying degrees of maturation, these cells still differ from deceased donor human β cells in several respects. We sought to develop a reporter cell line that could be used to dynamically track SCβ cell functional maturation.

HumanIslets: An integrated platform for human islet data access and analysis.

Comprehensive molecular and cellular phenotyping of human islets can enable deep mechanistic insights for diabetes research. We established the Human Islet Data Analysis and Sharing (HI-DAS) consortium to advance goals in accessibility, usability, and integration of data from human islets isolated from donors with and without diabetes at the Alberta Diabetes Institute (ADI) IsletCore. Here we introduce HumanIslets.

Top-Down Proteomics of Mouse Islets With Beta Cell CPE Deletion Reveals Molecular Details in Prohormone Processing.

Altered prohormone processing, such as with proinsulin and pro-islet amyloid polypeptide (proIAPP), has been reported as an important feature of prediabetes and diabetes. Proinsulin processing includes removal of several C-terminal basic amino acids and is performed principally by the exopeptidase carboxypeptidase E (CPE), and mutations in CPE or other prohormone convertase enzymes (PC1/3 and PC2) result in hyperproinsulinemia. A comprehensive characterization of the forms and quantities of improperly processed insulin and other hormone products following Cpe deletion in pancreatic islets has yet to be attempted.

Tregs with an MHC class II peptide-specific chimeric antigen receptor prevent autoimmune diabetes in mice.

Adoptive immunotherapy with Tregs is a promising approach for preventing or treating type 1 diabetes. Islet antigen-specific Tregs have more potent therapeutic effects than polyclonal cells, but their low frequency is a barrier for clinical application. To generate Tregs that recognize islet antigens, we engineered a chimeric antigen receptor (CAR) derived from a monoclonal antibody with specificity for the insulin B chain 10-23 peptide presented in the context of the IAg7 MHC class II allele present in NOD mice.

Residual β-Cell Function Is Associated With Longer Time in Range in Individuals With Type 1 Diabetes.

Objective: Little is known about the influence of residual islet function on glycemic control in type 1 diabetes (T1D). We investigated the associations between residual β-cell function and metrics of continuous glucose monitoring (CGM) in individuals with T1D.

Research Design And Methods: In this cross-sectional cohort comprising 489 individuals (64% female, age 41.

Management of Brachial Plexus Birth Injuries at British Columbia Children's Hospital.

A multidisciplinary team at BC Children's Hospital provides brachial plexus birth injury management for our provincial catchment area. Although compared with many centers we service a relatively small clinic population, we have the benefit of universal health care, province-wide reach, and accessible research infrastructure. In 2008, we created the Sup-ER protocol, which includes an orthosis that passively positions the neonatal shoulder into more idealized glenohumeral contact during early growth.

How Institution of the Sup-ER Protocol in a Clinic Changed Procedure Patterns in Upper Brachial Plexus (Erb's Type) Birth Injuries.

Background: For children with upper brachial plexus birth injury (BPBI; C5, C6, ±C7 roots), most clinics first recommend nonsurgical treatment followed by primary and/or secondary surgical interventions in selected patients. Since 2008, we have used an infant shoulder repositioning protocol (supination-external rotation [Sup-ER]) designed to prevent shoulder internal rotation contracture and its potential effects on the shoulder joint. This study characterizes our clinic's current choice, number, and timing of primary and secondary procedural interventions (including Botox) and compares Sup-ER protocol patients with those of our historical controls.

Deletion of Carboxypeptidase E in β-Cells Disrupts Proinsulin Processing but Does Not Lead to Spontaneous Development of Diabetes in Mice.

Unlabelled: Carboxypeptidase E (CPE) facilitates the conversion of prohormones into mature hormones and is highly expressed in multiple neuroendocrine tissues. Carriers of CPE mutations have elevated plasma proinsulin and develop severe obesity and hyperglycemia. We aimed to determine whether loss of Cpe in pancreatic β-cells disrupts proinsulin processing and accelerates development of diabetes and obesity in mice.

Strategies for optimizing CITE-seq for human islets and other tissues.

Defining the immunological landscape of human tissue is an important area of research, but challenges include the impact of tissue disaggregation on cell phenotypes and the low abundance of immune cells in many tissues. Here, we describe methods to troubleshoot and standardize Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq) for studies involving enzymatic digestion of human tissue. We tested epitope susceptibility of 92 antibodies commonly used to differentiate immune lineages and cell states on human peripheral blood mononuclear cells following treatment with an enzymatic digestion cocktail used to isolate islets.

Insulin B peptide-MHC class II-specific chimeric antigen receptor-Tregs prevent autoimmune diabetes.

Unlabelled: Adoptive immunotherapy with Tregs is a promising approach for prevention or treatment of type 1 diabetes. Islet antigen-specific Tregs have more potent therapeutic effects than polyclonal cells, but their low frequency is a barrier for clinical application. To generate Tregs that recognize islet antigens, we engineered a chimeric antigen receptor (CAR) derived from a monoclonal antibody with specificity for the insulin B-chain 10-23 peptide presented in the context of the IA MHC class II allele present in NOD mice.

A small molecule improves diabetes in mice expressing human islet amyloid polypeptide.

In recent years, the number of studies on islet and beta cell autophagy have substantially increased due to growing interest in the role of autophagy in maintaining cellular homeostasis in diabetes. In type 2 diabetes, human islet amyloid polypeptide (hIAPP) aggregates to form higher structure oligomers and fibrils that are toxic to beta cells and induce islet inflammation. The primary mechanism of oligomer and fibril clearance in beta cells is through the autophagic pathway, a process that is impaired in type 2 diabetes.

Islet amyloid polypeptide does not suppress pancreatic cancer.

Objectives: Pancreatic cancer risk is elevated approximately two-fold in type 1 and type 2 diabetes. Islet amyloid polypeptide (IAPP) is an abundant beta-cell peptide hormone that declines with diabetes progression. IAPP has been reported to act as a tumour-suppressor in p53-deficient cancers capable of regressing tumour volumes.

SORLA mediates endocytic uptake of proIAPP and protects against islet amyloid deposition.

Objective: Sorting-related receptor with type A repeats (SORLA) is a neuronal sorting receptor that prevents accumulation of amyloid-beta peptides, the main constituent of senile plaques in Alzheimer disease. Recent transcriptomic studies show that SORLA transcripts are also found in beta cells of pancreatic islets, yet the role of SORLA in islets is unknown. Based on its protective role in reducing the amyloid burden in the brain, we hypothesized that SORLA has a similar function in the pancreas via regulation of amyloid formation from islet amyloid polypeptide (IAPP).

Something Stinks! Finding Ways to Manage Noxious Odours in the Operating Room and Other Clinical Settings A Randomized Controlled Trial.

The hospital can be saturated with noxious smells. Anecdotally, medical staff apply products to surgical masks to lessen the impact of these smells. This study aimed to determine the odour-masking ability of 4 inexpensive and convenient products.

Gut-derived bacterial flagellin induces beta-cell inflammation and dysfunction.

Hyperglycemia and type 2 diabetes (T2D) are caused by failure of pancreatic beta cells. The role of the gut microbiota in T2D has been studied, but causal links remain enigmatic. Obese individuals with or without T2D were included from two independent Dutch cohorts.

Elevated islet prohormone ratios as indicators of insulin dependency in auto-islet transplant recipients.

Pancreatic islet transplantation has therapeutic potential in type 1 diabetes and is also an established therapy in chronic pancreatitis. However, the long-term transplant outcomes are modest. Identifying indicators of graft function will aid the preservation of transplanted islets and glycemic control.

Insulin Null β-cells Have a Prohormone Processing Defect That Is Not Reversed by AAV Rescue of Proinsulin Expression.

Up to 6% of diabetes has a monogenic cause including mutations in the insulin gene, and patients are candidates for a gene therapy. Using a mouse model of permanent neonatal diabetes, we assessed the efficacy of an adeno-associated virus (AAV)-mediated gene therapy. We used AAVs with a rat insulin 1 promoter (Ins1) regulating a human insulin gene (INS; AAV Ins1-INS) or native mouse insulin 1 (Ins1; AAV Ins-Ins1) to deliver an insulin gene to β-cells of constitutive insulin null mice (Ins1-/-Ins2-/-) and adult inducible insulin-deficient mice [Ins1-/-Ins2f/f PdxCreER and Ins1-/-Ins2f/f mice administered AAV Ins1-Cre)].

Heterogeneity of Diabetes: β-Cells, Phenotypes, and Precision Medicine: Proceedings of an International Symposium of the Canadian Institutes of Health Research's Institute of Nutrition, Metabolism and Diabetes and the U.S. National Institutes of Health's National Institute of Diabetes and Digestive and Kidney Diseases.

One hundred years have passed since the discovery of insulin-an achievement that transformed diabetes from a fatal illness into a manageable chronic condition. The decades since that momentous achievement have brought ever more rapid innovation and advancement in diabetes research and clinical care. To celebrate the important work of the past century and help to chart a course for its continuation into the next, the Canadian Institutes of Health Research's Institute of Nutrition, Metabolism and Diabetes and the U.

Heterogeneity of Diabetes: β-Cells, Phenotypes, and Precision Medicine: Proceedings of an International Symposium of the Canadian Institutes of Health Research's Institute of Nutrition, Metabolism and Diabetes and the U.S. National Institutes of Health's National Institute of Diabetes and Digestive and Kidney Diseases.

One hundred years have passed since the discovery of insulin-an achievement that transformed diabetes from a fatal illness into a manageable chronic condition. The decades since that momentous achievement have brought ever more rapid innovation and advancement in diabetes research and clinical care. To celebrate the important work of the past century and help to chart a course for its continuation into the next, the Canadian Institutes of Health Research's Institute of Nutrition, Metabolism and Diabetes and the U.

Heterogeneity of Diabetes: β-Cells, Phenotypes, and Precision Medicine: Proceedings of an International Symposium of the Canadian Institutes of Health Research's Institute of Nutrition, Metabolism and Diabetes and the U.S. National Institutes of Health's National Institute of Diabetes and Digestive and Kidney Diseases.

One hundred years have passed since the discovery of insulin-an achievement that transformed diabetes from a fatal illness into a manageable chronic condition. The decades since that momentous achievement have brought ever more rapid innovation and advancement in diabetes research and clinical care. To celebrate the important work of the past century and help to chart a course for its continuation into the next, the Canadian Institutes of Health Research's Institute of Nutrition, Metabolism and Diabetes and the U.