Conversion of pancreatic α cells into insulin-producing cells modulated by β-cell insufficiency and supplemental insulin administration

Katahira, Takehiro; Miyatsuka, Takeshi; Miura, Masaki; Suzuki, Luka; Himuro, Miwa; Nishida, Yuya; Satoh, Hiroaki; Watada, Hirotaka

doi:10.1016/j.bbrc.2019.10.100

Cited by 7 publications

(7 citation statements)

References 15 publications

(22 reference statements)

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“…It has been reported that extreme β-cell ablation induces α-to-β conversion in mice 7 , 8 . To investigate whether β-cell ablation affects the reprogramming efficiency and/or the characteristics of reprogrammed β cells in our experimental model, we induced β-cell ablation by injecting alloxan (ALX) into αPdx1; Stat3 KO mice and control αPdx1; Stat3 Hetero mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Another key to enhance cellular reprogramming into β cells is the extreme ablation of β cells, as previously demonstrated 7 , 8 . To further investigate the effects of β-cell ablation on α-to-β reprogramming, we induced the ectopic expression of PDX1 in α cells combined with β-cell ablation by injecting alloxan, demonstrating that extreme β-cell loss robustly enhances α-to-β reprogramming induced by Pdx1, although there was no additive effect by Stat3 inhibition.…”

Section: Introductionmentioning

confidence: 98%

“…We consider that α cells are a prime candidate for reprogramming into β cells, because they are developmentally closely related to β cells. Notably, mouse islet α cells transdifferentiate into β cells under conditions of extreme β-cell loss, which is a condition similar to type 1 diabetes 7 , 8 . We and others have previously shown that the ectopic expression of β-cell specific transcription factors, pancreatic and duodenal homeobox 1 (PDX1) and musculoaponeurotic fibrosarcoma oncogene family A (MAFA), converts both embryonic or adult α cells into insulin-producing cells in mice 9 , 10 .…”

Section: Introductionmentioning

confidence: 99%

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STAT3 suppression and β-cell ablation enhance α-to-β reprogramming mediated by Pdx1

Wakabayashi

Miyatsuka

Miura

et al. 2022

Sci Rep

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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STAT3 suppression and β-cell ablation enhance α-to-β reprogramming mediated by Pdx1

Wakabayashi

Miyatsuka

Miura

et al. 2022

Sci Rep

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“…Weight loss, polyphagia, polyuria and polydipsia are the main features of T1DM ( Bibak et al, 2014 ). Numerous studies have shown that alloxan destroys insulin-producing β-cells, a chemical commonly used in laboratories to make diabetic models ( Katahira et al, 2020 ). Administration of RBPP-P (100 mg/kg) for 4 weeks showed marked hypoglycemic effect in ALX-induced diabetic mice.…”

Section: Discussionmentioning

confidence: 99%

Bee Pollen Polysaccharide From Rosa rugosa Thunb. (Rosaceae) Promotes Pancreatic β-Cell Proliferation and Insulin Secretion

Yang

Chen

et al. 2021

Front. Pharmacol.

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Insufficient pancreatic β-cell or insulin-producing β-cell are implicated in all types of diabetes mellitus. Our previous studies showed bee pollen polysaccharide RBPP-P improves insulin resistance in type 2 diabetic mice by inhibiting liver fat deposition. However, its potential of regulating β-cell function and integrity is not fully known. Herein, we observed that β-cell proliferation (n = 10), insulin synthesis (n = 5, p = 0.01684) and insulin incretion (n = 5, p = 0.02115) were intensely activated in MIN6 cells when treatment with RBPP-P. In alloxan-induced diabetic mice, oral administration of RBPP-P (n = 10) effectively decreased the blood glucose (p = 0.0326), drink intake (p < 0.001) and urine (p < 0.001). It directly stimulated phosphorylation of p38 (p = 0.00439), ERK (p = 0.02951) and AKT (p = 0.0072) to maintain the islet function and mass. Thus, our data suggest that RBPP-P is a natural compound to regulate β-cell proliferation and function, indicating it might have therapeutic potential against type 1 diabetes.

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“…NEUROG3+ EPs give rise to all five types of pancreatic endocrine cells (α-, β-, δ-, ϵ-, and PP-cells). Each of these endocrine cell types synthesizes and secretes one hormone, i.e., glucagon (α-cells), insulin (β-cells), somatostatin (δ-cells), ghrelin (ϵ-cells), and PP (PP-cells), although multihormonal cells are observed in both humans and mice [ 39 - 41 ]. The specification of these cell types is regulated by the orchestrated expression of transcription factors that trigger islet cell type-specific gene regulatory networks, and represses alternative networks to maintain cell identities [ 20 , 33 , 42 ].…”

Section: Pancreas Developmentmentioning

confidence: 99%

Heterogeneity of Islet Cells during Embryogenesis and Differentiation

Sasaki

Miyatsuka

2023

Diabetes Metab J

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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.

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Conversion of pancreatic α cells into insulin-producing cells modulated by β-cell insufficiency and supplemental insulin administration

Cited by 7 publications

References 15 publications

STAT3 suppression and β-cell ablation enhance α-to-β reprogramming mediated by Pdx1

STAT3 suppression and β-cell ablation enhance α-to-β reprogramming mediated by Pdx1

Bee Pollen Polysaccharide From Rosa rugosa Thunb. (Rosaceae) Promotes Pancreatic β-Cell Proliferation and Insulin Secretion

Heterogeneity of Islet Cells during Embryogenesis and Differentiation

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