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Open AccessJournal ArticleDOI

Conversion of adult pancreatic α-cells to β-cells after extreme β-cell loss

TLDR
In this article, a transgenic model of diphtheria-toxin-induced acute selective near-total beta-cell ablation was used to investigate whether adult mammals can differentiate (regenerate) new beta-cells after extreme, total β-cell loss, as in diabetes.
Abstract
Pancreatic insulin-producing beta-cells have a long lifespan, such that in healthy conditions they replicate little during a lifetime. Nevertheless, they show increased self-duplication after increased metabolic demand or after injury (that is, beta-cell loss). It is not known whether adult mammals can differentiate (regenerate) new beta-cells after extreme, total beta-cell loss, as in diabetes. This would indicate differentiation from precursors or another heterologous (non-beta-cell) source. Here we show beta-cell regeneration in a transgenic model of diphtheria-toxin-induced acute selective near-total beta-cell ablation. If given insulin, the mice survived and showed beta-cell mass augmentation with time. Lineage-tracing to label the glucagon-producing alpha-cells before beta-cell ablation tracked large fractions of regenerated beta-cells as deriving from alpha-cells, revealing a previously disregarded degree of pancreatic cell plasticity. Such inter-endocrine spontaneous adult cell conversion could be harnessed towards methods of producing beta-cells for diabetes therapies, either in differentiation settings in vitro or in induced regeneration.

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Journal ArticleDOI

Sequential introduction and dosage balance of defined transcription factors affect reprogramming efficiency from pancreatic duct cells into insulin-producing cells

TL;DR: In vitro screening with the mPac-MIP-RFP reporter cell line demonstrated that the timing and dosage of gene delivery with defined transcription factors influence the reprogramming efficiency.
Journal ArticleDOI

Molecular Therapeutics of Pancreatic Ductal Adenocarcinoma: Targeted Pathways and the Role of Cancer Stem Cells.

TL;DR: The role of CSCs and tumour stroma in developing therapeutic strategies for PDAC is described and it is suggested that developmental plasticity could be considered a hallmark of cancers and targeting epigenetic mechanisms opens therapeutic routes for heterogeneous cancer cell populations.
Journal ArticleDOI

High-fat diet impacts more changes in beta-cell compared to alpha-cell transcriptome

TL;DR: It is concluded that alpha cell transcriptome is less reactive to HFD diet compared to beta cells and display adaptations to cellular stress and exocytosis.
Journal ArticleDOI

Pancreatic β-cell heterogeneity in health and diabetes: classes, sources, and subtypes.

TL;DR: In this article, the authors studied how pancreatic β-cells behave in healthy and stressful conditions, a process at the center of type 2 diabetes etiology, and found that β-cell performance in healthy conditions is similar to that in stressful conditions.
Journal ArticleDOI

Regenerative medicine using adult neural stem cells: the potential for diabetes therapy and other pharmaceutical applications

TL;DR: The utilization of autologous cells from patients with diabetes may address challenges regarding the compatibility of donor tissues as well as provide the means to naturally and safely restore function, reducing future risks while also providing a long-term cure.
References
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Book

Manipulating the mouse embryo: A laboratory manual

TL;DR: Here are recorded the tech- niques for preparing, inserting and analysing DNA sequences, for retroviral infection of mice, for production and use of EC and EK cells as vehicles for engineered sequences and for nuclear transplantation - all against a background of the basic procedures required for pro- ducing and handling the em- bryos.
Journal ArticleDOI

Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus

TL;DR: In contrast to existing lacZ reporter lines, where lacZ expression cannot easily be detected in living tissue, the EYFP and ECFP reporter strains are useful for monitoring the expression of Cre and tracing the lineage of these cells and their descendants in cultured embryos or organs.
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Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation.

TL;DR: This work introduces a method for genetic lineage tracing to determine the contribution of stem cells to a tissue of interest and suggests that terminally differentiated β-cells retain a significant proliferative capacity in vivo and casts doubt on the idea that adult stem cells have a significant role in β-cell replenishment.
Journal ArticleDOI

In vivo reprogramming of adult pancreatic exocrine cells to beta-cells.

TL;DR: This study identifies a specific combination of three transcription factors (Ngn3) Pdx1 and Mafa that reprograms differentiated pancreatic exocrine cells in adult mice into cells that closely resemble β-cells, and suggests a general paradigm for directing cell reprogramming without reversion to a pluripotent stem cell state.
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Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats.

TL;DR: It is reported that exendin-4, a long-acting GLP-I agonist, stimulates both the differentiation of beta-cells from ductal progenitor cells (neogenesis) and proliferation of Beta-cells when administered to rats and holds promise as a novel therapy to stimulate beta-cell growth and differentiation when administer to diabetic individuals with reduced beta- cell mass.
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