Pathogenesis of Type 1 Diabetes, Stem Cell-derived islets and Imaging
Type 1 diabetes is a heterogeneous autoimmune inflammatory disease characterised by immune cell infiltration of the pancreatic islets, leading to progressive β-cell dysfunction and loss.
Human stem cell-derived islets are an emerging source of functional β cells and are currently being evaluated in clinical trials as a promising cell replacement therapy to restore insulin production.
Despite advances in research imaging, including approaches to track transplanted stem cell-derived islets, there are currently no clinically approved techniques for direct monitoring of pancreatic autoimmune activity or disease progression.
Group Leader, Esteban Gurzov, Ph.D.
Research Interests
Protein tyrosine phosphatases in β-cell dysfunction and type 1 diabetes
Protein tyrosine phosphatases (PTPs) are key regulators of β-cell signalling, function, and survival, and their dysregulation contributes to type 1 diabetes. Genetic variants in PTPN2, PTPN22, and PTPRK are associated with autoimmune disease susceptibility.
PTPs are expressed in pancreatic islets and maintain signalling pathways essential for β-cell homeostasis. In type 1 diabetes, inflammatory and oxidative stress can inactivate PTPs, leading to impaired β-cell function, cell death, and altered immune interactions, including antigen presentation.
Our work indicates that disrupted PTP activity links inflammation, antigen presentation, and β-cell failure in autoimmunity. Understanding these pathways may identify new strategies to preserve β-cell function and delay disease progression. (Figure adapted from Gurzov EN, et al. TEM 2015)
Engineering human stem cell-derived islets
The Signal Transduction & Metabolism Laboratory takes advantage of gene editing in human stem cell-derived islets to study the molecular mechanisms of type 1 diabetes and develop new therapeutic strategies. Human pluripotent stem cells are differentiated into insulin-producing β cells and islet organoids that mimic native pancreatic islets.
Our research identifies pathways regulating β-cell development, function, stress responses, and survival, particularly under inflammatory conditions relevant to type 1 diabetes. We combine stem cell models with genome editing, functional genomics, and advanced imaging to study how genetic and environmental factors drive β-cell dysfunction and immune-mediated damage.
We also aim to improve the maturation and resilience of stem cell-derived islets for future cell replacement therapies. These approaches help advance understanding of diabetes pathogenesis and support strategies to preserve or restore functional β-cell mass in type 1 diabetes. (Figure adapted from Negueruela J, et al. Star Protocols 2024)
“Lighting Up” and tracking native β cells and stem cell-derived islets
Early diagnosis of type 1 diabetes is limited by the lack of reliable methods to directly measure pancreatic β-cell mass. In clinical practice, β-cell function is estimated using serum C-peptide, which does not accurately reflect true β-cell mass, particularly in early type 1 diabetes.
State-of-the-art approaches are now focused on molecular imaging probes and fluorescent biosensors, including emerging biosensor-based platforms for monitoring cellular metabolism at high resolution. In parallel, imaging strategies are being developed to track transplanted stem cell-derived islets.
Our work aims to develop β-cell-specific imaging tools, including peptide-based probes and genetically encoded biosensors such as the HYlight platform, to visualise and monitor metabolic function in both native and stem cell-derived β-cells. These multidisciplinary approaches combine 3D and real-time imaging, structural biology, and in vivo validation to enable non-invasive assessment of β-cell mass and islet graft function. (Figure adapted from Gurzov EN, et al. TEM 2020)
Selected Publications
Negueruela J, Vandenbempt V, Talamantes S, Ribeiro-Costa F, Nunes M, Dias A, Bansal M, Gurzov EN. Protocol for CRISPR-Cas12a genome editing of protein tyrosine phosphatases in human pluripotent stem cells and functional β-like cell generation. STAR Protocols 5(3):103297, 2024
Vandenbempt V, Eski SE, Brahma MK, Negueruela J, Bruggeman Y, Demine S, Xiao P, Cardozo AK, Baeyens N, Martelotto LG, Singh SP, Mariño E, Gysemans C, Gurzov EN. HAMSAB diet ameliorates dysfunctional signalling in pancreatic islets in autoimmune diabetes. iScience 27(1):108694, 2023
Elvira B, Vandenbempt V, Bauzá-Martinez J, Crutzen R, Negueruela J, Ibrahim H, Winder ML, Brahma MK, Vekeriotaite B, Martens PJ, Singh SP, Rossello F, Lybaert P, Otonkoski T, Gysemans C, Wu W, Gurzov EN. PTPN2 Regulates the Interferon Signaling and Endoplasmic Reticulum Stress Response in Pancreatic β-Cells in Autoimmune Diabetes. Diabetes 71(4):653-668, 2022
Eriksson M, Litwak SA, Yun Y, Stanley WJ, Thorn P, Ahlgren U, Gurzov EN. Insulin-Binding Peptide Probes Provide a Novel Strategy for Pancreatic β-Cell Imaging. Mol Pharm online, 2021
Gurzov EN, Ke PC, Ahlgren U, Garcia Ribeiro RS, Gotthardt M. Novel Strategies to Protect and Visualize Pancreatic β Cells in Diabetes. Trends Endocrinol Metab 31(12):905-917, 2020
Stanley WJ, Trivedi PM, Sutherland AP, Thomas HE, Gurzov EN. Differential regulation of pro-inflammatory cytokine signalling by protein tyrosine phosphatases in pancreatic β-cells. J Mol Endocrinology 59:325-337, 2017
Gurzov EN, Stanley WJ, Brodnicki TC, Thomas HE. Protein tyrosine phosphatases: molecular switches in metabolism and diabetes. Trends Endocrinol Metab 26:30-39, 2015
Stanley WJ, Litwak SA, Quah HS, Tan SM, Kay TW, Tiganis T, de Haan JB, Thomas HE, Gurzov EN. Inactivation of protein tyrosine phosphatases enhances interferon signaling in pancreatic islets. Diabetes 64:2489-2496, 2015
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