“…3 B). As insulin/glucagon double-positive cells are thought to be immature cells in the developing pancreas 20 , this finding suggests that Stat3 suppression enhanced more advanced α-to-β conversion induced by Pdx1. Figure 3 The Characteristics of α-cell-derived insulin-producing cells.…”
As diabetes results from the absolute or relative deficiency of insulin secretion from pancreatic β cells, possible methods to efficiently generate surrogate β cells have attracted a lot of efforts. To date, insulin-producing cells have been generated from various differentiated cell types in the pancreas, such as acinar cells and α cells, by inducing defined transcription factors, such as PDX1 and MAFA, yet it is still challenging as to how surrogate β cells can be efficiently generated for establishing future regenerative therapies for diabetes. In this study, we demonstrated that the exogenous expression of PDX1 activated STAT3 in α cells in vitro, and STAT3-null PDX1-expressing α cells in vivo resulted in efficient induction of α-to-β reprogramming, accompanied by the emergence of α-cell-derived insulin-producing cells with silenced glucagon expression. Whereas β-cell ablation by alloxan administration significantly increased the number of α-cell-derived insulin-producing cells by PDX1, STAT3 suppression resulted in no further increase in β-cell neogenesis after β-cell ablation. Thus, STAT3 modulation and β-cell ablation nonadditively enhance α-to-β reprogramming induced by PDX1, which may lead to the establishment of cell therapies for curing diabetes.
“…3 B). As insulin/glucagon double-positive cells are thought to be immature cells in the developing pancreas 20 , this finding suggests that Stat3 suppression enhanced more advanced α-to-β conversion induced by Pdx1. Figure 3 The Characteristics of α-cell-derived insulin-producing cells.…”
As diabetes results from the absolute or relative deficiency of insulin secretion from pancreatic β cells, possible methods to efficiently generate surrogate β cells have attracted a lot of efforts. To date, insulin-producing cells have been generated from various differentiated cell types in the pancreas, such as acinar cells and α cells, by inducing defined transcription factors, such as PDX1 and MAFA, yet it is still challenging as to how surrogate β cells can be efficiently generated for establishing future regenerative therapies for diabetes. In this study, we demonstrated that the exogenous expression of PDX1 activated STAT3 in α cells in vitro, and STAT3-null PDX1-expressing α cells in vivo resulted in efficient induction of α-to-β reprogramming, accompanied by the emergence of α-cell-derived insulin-producing cells with silenced glucagon expression. Whereas β-cell ablation by alloxan administration significantly increased the number of α-cell-derived insulin-producing cells by PDX1, STAT3 suppression resulted in no further increase in β-cell neogenesis after β-cell ablation. Thus, STAT3 modulation and β-cell ablation nonadditively enhance α-to-β reprogramming induced by PDX1, which may lead to the establishment of cell therapies for curing diabetes.
“…We also found that somatostatin (Sst)-expressing cells, which are in an intermediate state during β-cell differenpage 5 of 12 Heterogeneity of developing islet cells Diabetes Metab J 2023 Forthcoming. Posted online 2023 https://e-dmj.org tiation in both mice and humans, express high levels of Vim [65]. These EMT markers are lost in late EPs and hormone-expressing endocrine cells [46,67].…”
Section: Heterogeneity Of Endocrine Cell Developmentmentioning
confidence: 99%
“…In addition, β-cell subpopulations with higher glucose responsiveness have been reported, such as flattop (Fltp) + [75], CD9-/ST8 alpha-N-acetyl-neuraminide alpha-2,8sialyltransferase 1 (ST8SIA1)- [86], ectonucleoside triphosphate diphosphohydrolase 3 (ENTPD3)+ [87][88][89], and protocadherin 7 (PCDH7)+ cells [90]. Although many researchers have tried to detect and quantify β-cell genesis in adult islets, it has rarely been detected in the pancreas of adult mice, indicating that β-cell mass is maintained almost exclusively by self-renewal [65,69,91]. On the other hand, rare pancreatic-cell populations have also been identified by scRNA-seq.…”
Section: Heterogeneity Of Maturing and Adult Beta Cellsmentioning
Diabetes is caused by insufficient insulin secretion due to β-cell dysfunction and/or β-cell loss. Therefore, the restoration of functional β-cells by the induction of β-cell differentiation from embryonic stem (ES) and induced-pluripotent stem (iPS) cells, or from somatic non-β-cells, may be a promising curative therapy. To establish an efficient and feasible method for generating functional insulin-producing cells, comprehensive knowledge of pancreas development and β-cell differentiation, including the mechanisms driving cell fate decisions and endocrine cell maturation is crucial. Recent advances in single-cell RNA sequencing (scRNA-seq) technologies have opened a new era in pancreas development and diabetes research, leading to clarification of the detailed transcriptomes of individual insulin-producing cells. Such extensive high-resolution data enables the inference of developmental trajectories during cell transitions and gene regulatory networks. Additionally, advancements in stem cell research have not only enabled their immediate clinical application, but also has made it possible to observe the genetic dynamics of human cell development and maturation in a dish. In this review, we provide an overview of the heterogeneity of islet cells during embryogenesis and differentiation as demonstrated by scRNA-seq studies on the developing and adult pancreata, with implications for the future application of regenerative medicine for diabetes.
“…С помощью нокаутных и трансгенных мышей получено понимание того, какие факторы транскрипции участвуют в развитии поджелудочной железы и каковы пути передачи сигналов инсулина. Тканеспецифические нокауты оказались особенно полезными при изучении передачи сигналов инсулина, поскольку мыши с глобальным нокаутом рецептора инсулина нежизнеспособны [119][120][121][122][123].…”
Section: модели без ожиренияunclassified
“…The use of knockout and transgenic mice made it possible to identify the transcription factors involved in the pancreas development and insulin signaling pathways. Tissue-specific knockouts turned out to be particularly useful in studying insulin signaling, since mice with global knockout of the insulin receptor are not viable [ 119 , 120 , 121 , 122 , 123 ].…”
Type 2 diabetes mellitus (T2DM) is the most common endocrine disorder (90%) in the world; it has numerous clinical, immunological, and genetic differences from type 1 diabetes mellitus. The pathogenesis of T2DM is complex and not fully clear. To date, animal models remain the main tool by which to study the pathophysiology and therapy of T2DM. Rodents are considered the best choice among animal models, because they are characterized by a small size, short induction period, easy diabetes induction, and economic efficiency. This review summarizes data on experimental models of T2DM that are currently used, evaluates their advantages and disadvantages vis-a-vis research, and describes in detail the factors that should be taken into account when using these models. Selection of a suitable model for tackling a particular issue is not always trivial; it affects study results and their interpretation.
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