Pancreatic Progenitors: There and Back Again

Domínguez‐Bendala, Juan; Qadir, Mirza Muhammad Fahd; Pastori, Ricardo L.

doi:10.1016/j.tem.2018.10.002

Cited by 26 publications

(22 citation statements)

References 73 publications

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“…The case for neogenesis, especially in basal conditions, has been much more controversial, with almost an equal number of studies providing evidence to support the neogenesis hypothesis as there are refuting it (reviewed in [ 38 ]). One major hindrance to these studies has been the failure to identify a stem cell marker that would allow for lineage tracing to clearly identify newly formed beta cells.…”

Section: Intrinsic Beta Cell Mass Expansionmentioning

confidence: 99%

Islet Regeneration: Endogenous and Exogenous Approaches

Docherty

Sussel

2021

IJMS

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Both type 1 and type 2 diabetes are characterized by a progressive loss of beta cell mass that contributes to impaired glucose homeostasis. Although an optimal treatment option would be to simply replace the lost cells, it is now well established that unlike many other organs, the adult pancreas has limited regenerative potential. For this reason, significant research efforts are focusing on methods to induce beta cell proliferation (replication of existing beta cells), promote beta cell formation from alternative endogenous cell sources (neogenesis), and/or generate beta cells from pluripotent stem cells. In this article, we will review (i) endogenous mechanisms of beta cell regeneration during steady state, stress and disease; (ii) efforts to stimulate endogenous regeneration and transdifferentiation; and (iii) exogenous methods of beta cell generation and transplantation.

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Section: Intrinsic Beta Cell Mass Expansionmentioning

confidence: 99%

Islet Regeneration: Endogenous and Exogenous Approaches

Docherty

Sussel

2021

IJMS

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“…In recent years, the transdifferentiation of pancreatic endocrine cells into beta cells was proved to be a promising method [34]. After a decade of relative discredit, the progenitor cell hypothesis made a figurative journey back into favor [35]. In our study, we assessed the three origins of newborn beta cells, including beta cell self-replication, alpha to beta cell transdifferentiation and duct-derived beta cell neogenesis, and found that all the three paths contributed to the dapagliflozininduced beta cell regeneration.…”

Section: Protective Effects Of Sglt2 Inhibitors On Pancreatic Beta Cellsmentioning

confidence: 99%

Dapagliflozin promotes beta cell regeneration by inducing pancreatic endocrine cell phenotype conversion in type 2 diabetic mice

et al. 2020

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Background: Clinical trials and animal studies have shown that sodium-glucose co-transporter type 2 (SGLT2) inhibitors improve pancreatic beta cell function. Our study aimed to investigate the effect of dapagliflozin on islet morphology and cell phenotype, and explore the origin and possible reason of the regenerated beta cells. Methods: Two diabetic mouse models, db/db mice and pancreatic alpha cell lineage-tracing (glucagon-β-gal) mice whose diabetes was induced by high fat diet combined with streptozotocin, were used. Mice were treated by daily intragastric administration of dapagliflozin (1 mg/kg) or vehicle for 6 weeks. The plasma insulin, glucagon and glucagon-like peptide-1 (GLP-1) were determined by using ELISA. The evaluation of islet morphology and cell phenotype was performed with immunofluorescence. Primary rodent islets and αTC1.9, a mouse alpha cell line, were incubated with dapagliflozin (0.25-25 μmol/L) or vehicle in the presence or absence of GLP-1 receptor antagonist for 24 h in regular or high glucose medium. The expression of specific markers and hormone levels were determined. Results: Treatment with dapagliflozin significantly decreased blood glucose in the two diabetic models and upregulated plasma insulin and GLP-1 levels in db/db mice. The dapagliflozin treatment increased islet and beta cell numbers in the two diabetic mice. The beta cell proliferation as indicated by C-peptide and BrdU doublepositive cells was boosted by dapagliflozin. The alpha to beta cell conversion, as evaluated by glucagon and insulin double-positive cells and confirmed by using alpha cell lineage-tracing, was facilitated by dapagliflozin. After the dapagliflozin treatment, some insulin-positive cells were located in the duct compartment or even colocalized with duct cell markers, suggestive of duct-derived beta cell neogenesis. In cultured primary rodent islets and αTC1.9 cells, dapagliflozin upregulated the expression of pancreatic endocrine progenitor and beta cell specific markers (including Pdx1) under high glucose condition. Moreover, dapagliflozin upregulated the expression of Pcsk1 (which encodes prohormone convertase 1/3, an important enzyme for processing proglucagon to GLP-1), and increased GLP-1 content and secretion in αTC1.9 cells. Importantly, the dapagliflozin-induced upregulation of Pdx1 expression was attenuated by GLP-1 receptor antagonist. Conclusions: Except for glucose-lowering effect, dapagliflozin has extra protective effects on beta cells in type 2 diabetes. Dapagliflozin enhances beta cell self-replication, induces alpha to beta cell conversion, and promotes duct-derived beta cell neogenesis. The promoting effects of dapagliflozin on beta cell regeneration may be partially mediated via GLP-1 secreted from alpha cells.

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“…Additionally, non-β endocrine cells, pancreatic exocrine cells, and even nonpancreatic cells such as intestinal enteroendocrine cells have been demonstrated to transdifferentiate into insulin-secreting cells by reprogramming in some cases (Thorel et al, 2010 ; Chen et al, 2014 ; Lemper et al, 2015 ). However, genetic lineage-tracing studies indicated that the exocrine compartment was unlikely to contribute to the formation of endocrine cells in vivo (Aguayo-Mazzucato and Bonner-Weir, 2018 ; Dominguez-Bendala et al, 2019 ). The current dominant view is that the replenishment of adult pancreatic β cells relies principally on their self-duplication instead of potential pancreatic stem cell differentiation (Dor et al, 2004 ).…”

Section: State-of-the-art Strategies To Establish Islet Organoidsmentioning

confidence: 99%

Islet organoid as a promising model for diabetes

Zhang

Song

et al. 2021

Protein Cell

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Studies on diabetes have long been hampered by a lack of authentic disease models that, ideally, should be unlimited and able to recapitulate the abnormalities involved in the development, structure, and function of human pancreatic islets under pathological conditions. Stem cell-based islet organoids faithfully recapitulate islet development in vitro and provide large amounts of three-dimensional functional islet biomimetic materials with a morphological structure and cellular composition similar to those of native islets. Thus, islet organoids hold great promise for modeling islet development and function, deciphering the mechanisms underlying the onset of diabetes, providing an in vitro human organ model for infection of viruses such as SARS-CoV-2, and contributing to drug screening and autologous islet transplantation. However, the currently established islet organoids are generally immature compared with native islets, and further efforts should be made to improve the heterogeneity and functionality of islet organoids, making it an authentic and informative disease model for diabetes. Here, we review the advances and challenges in the generation of islet organoids, focusing on human pluripotent stem cell-derived islet organoids, and the potential applications of islet organoids as disease models and regenerative therapies for diabetes.

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Pancreatic Progenitors: There and Back Again

Cited by 26 publications

References 73 publications

Islet Regeneration: Endogenous and Exogenous Approaches

Islet Regeneration: Endogenous and Exogenous Approaches

Dapagliflozin promotes beta cell regeneration by inducing pancreatic endocrine cell phenotype conversion in type 2 diabetic mice

Islet organoid as a promising model for diabetes

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