The maintenance of pancreatic islet architecture is crucial for proper beta-cell function. We previously reported that disruption of human islet integrity could result in altered beta-cell identity... Show moreThe maintenance of pancreatic islet architecture is crucial for proper beta-cell function. We previously reported that disruption of human islet integrity could result in altered beta-cell identity. Here we combine beta-cell lineage tracing and single-cell transcriptomics to investigate the mechanisms underlying this process in primary human islet cells. Using drug-induced ER stress and cytoskeleton modification models, we demonstrate that altering the islet structure triggers an unfolding protein response that causes the downregulation of beta-cell maturity genes. Collectively, our findings illustrate the close relationship between endoplasmic reticulum homeostasis and beta-cell phenotype, and strengthen the concept of altered beta-cell identity as a mechanism underlying the loss of functional beta-cell mass. Show less
Groen, N.; Leenders, F.; Mahfouz, A.; Munoz-Garcia, A.; Muraro, M.J.; Graaf, N. de; ... ; Carlotti, F. 2021
The maintenance of pancreatic islet architecture is crucial for proper β-cell function. We previously reported that disruption of human islet integrity could result in altered β-cell identity. Here... Show moreThe maintenance of pancreatic islet architecture is crucial for proper β-cell function. We previously reported that disruption of human islet integrity could result in altered β-cell identity. Here we combine β-cell lineage tracing and single-cell transcriptomics to investigate the mechanisms underlying this process in primary human islet cells. Using drug-induced ER stress and cytoskeleton modification models, we demonstrate that altering the islet structure triggers an unfolding protein response that causes the downregulation of β-cell maturity genes. Collectively, our findings illustrate the close relationship between endoplasmic reticulum homeostasis and β-cell phenotype, and strengthen the concept of altered β-cell identity as a mechanism underlying the loss of functional β-cell mass. Show less
Leenders, F.; Groen, N.; Graaf, N. de; Engelse, M.A.; Rabelink, T.J.; Koning, E.J.P. de; Carlotti, F. 2021
Pancreatic beta-cell failure is a critical event in the onset of both main types of diabetes mellitus but underlying mechanisms are not fully understood. beta-cells have low anti-oxidant capacity,... Show morePancreatic beta-cell failure is a critical event in the onset of both main types of diabetes mellitus but underlying mechanisms are not fully understood. beta-cells have low anti-oxidant capacity, making them more susceptible to oxidative stress. In type 1 diabetes (T1D), reactive oxygen species (ROS) are associated with pro-inflammatory conditions at the onset of the disease. Here, we investigated the effects of hydrogen peroxide-induced oxidative stress on human beta-cells. We show that primary human beta-cell function is decreased. This reduced function is associated with an ER stress response and the shuttling of FOXO1 to the nucleus. Furthermore, oxidative stress leads to loss of beta-cell maturity genes MAFA and PDX1, and to a concomitant increase in progenitor marker expression of SOX9 and HES1. Overall, we propose that oxidative stress-induced beta-cell failure may result from partial dedifferentiation. Targeting antioxidant mechanisms may preserve functional beta-cell mass in early stages of development of T1D. Show less
Trinanes, J.; Dijke, P. ten; Groen, N.; Hanegraaf, M.; Porrini, E.; Rodriguez-Rodriguez, A.E.; ... ; Vries, A.P.J. de 2020
Active maintenance of beta-cell identity through fine-tuned regulation of key transcription factors ensures beta-cell function. Tacrolimus, a widely used immunosuppressant, accelerates onset of... Show moreActive maintenance of beta-cell identity through fine-tuned regulation of key transcription factors ensures beta-cell function. Tacrolimus, a widely used immunosuppressant, accelerates onset of diabetes after organ transplantation, but underlying molecular mechanisms are unclear. Here we show that tacrolimus induces loss of human beta-cell maturity and beta-cell failure through activation of the BMP/SMAD signaling pathway when administered under mild metabolic stress conditions. Tacrolimus-induced phosphorylated SMAD1/5 acts in synergy with metabolic stress-activated FOXO1 through formation of a complex. This interaction is associated with reduced expression of the key beta-cell transcription factor MAFA and abolished insulin secretion, both in vitro in primary human islets and in vivo in human islets transplanted into high-fat diet-fed mice. Pharmacological inhibition of BMP signaling protects human beta-cells from tacrolimus-induced beta-cell dysfunction in vitro. Furthermore, we confirm that BMP/SMAD signaling is activated in protocol pancreas allograft biopsies from recipients on tacrolimus. To conclude, we propose a novel mechanism underlying the diabetogenicity of tacrolimus in primary human beta-cells. This insight could lead to new treatment strategies for new-onset diabetes and may have implications for other forms of diabetes. Show less
Pullen, T.J.; Groen, N.; Oudenaarden, A. van; Hodson, D.J.; Carlotti, F.; Rutter, G.A. 2018
