Temporal single-cell regeneration studies: the greatest thing since sliced pancreas?

The application of single-cell analytic techniques to the study of stem/progenitor cell niches supports the emerging view that pancreatic cell lineages are in a state of flux between differentiation stages. For all their value, however, such analyses merely offer a snapshot of the cellular palette of the tissue at any given time point. Conclusions about potential developmental/regeneration paths are solely based on bioinformatics inferences. In this context, the advent of new techniques for the long-term culture and lineage tracing of human pancreatic slices offers a virtual window into the native organ and presents the field with a unique opportunity to serially resolve pancreatic regeneration dynamics at the single-cell level.

Puerarin ameliorates hyperglycemia in HFD diabetic mice by promoting ß-cell neogenesis via GLP-1R signaling activation.

BACKGROUND: Diabetes is characterized by ß-cell loss and dysfunction. A strategy for diabetes treatment is to promote new ß-cell formation. Puerarin is an isoflavone from the root of Pueraria lobata (Willd.) Ohwi. Our previous study demonstrated puerarin could ameliorate hyperglycemia in diabetic mice. However, related mechanisms and potential roles of puerarin in ß-cell neogenesis have not been elucidated. PURPOSE: The present study aims to investigate whether anti-diabetic effect of puerarin is dependent on promoting ß-cell neogenesis via GLP-1R signaling activation. METHODS: A high-fat diet (HFD) induced diabetic mouse model was applied to investigate effects of puerarin in vivo, exendin-4 (GLP-1R agonist) and metformin were used as positive controls. Moreover, related mechanisms and GLP-1R downstream signal transduction were explored in isolated cultured mouse pancreatic ductal cells. RESULTS: Puerarin improved glucose homeostasis in HFD diabetic mice significantly. Markers of new ß-cell formation (insulin, PDX1 and Ngn3) were observed in pancreatic ducts of HFD mice treated by puerarin. Of note, efficacy of puerarin in vivo was suppressed by GLP-1R antagonist exendin9-39, but enhanced by exendin-4 respectively. In cultured mouse pancreatic ductal cells, puerarin induced expressions of insulin and PDX1, upregulated GLP-1R expression and activated ß-catenin and STAT3 subsequently. Expressions of insulin and PDX1 in ductal cells could be blocked by exendin9-39, or ß-catenin inhibitor ICG001, or JAK2 inhibitor AG490. CONCLUSION: These data clarified puerarin ameliorated hyperglycemia of HFD mice via a novel mechanism involved promoting ß-cell neogenesis. Our finding highlights the potential value of puerarin developing as an anti-diabetic agent.

Increased mast cell number is associated with a decrease in beta-cell mass and regeneration in type 2 diabetic rats.

The role of mast cells (MCs) in type 2 diabetes (T2D) is not thoroughly studied as much as in T1D. Therefore in the current study we investigated correlation between these cells and various parameters of islets of Langerhans (IOL) in rats which were equally divided (n = 40) into; control and diabetic groups. We detected a significantly increased (p < 0.05) MC count (MCC) in the diabetic IOL compared to the control, together with a noticeable intra-islet seeding of these cells which displayed a tryptase positive immunostaining. A significant positive correlation (p < 0.05) between MCC and the % of glucagon cells per islet was detected in DM, unlike mass of the islets, mass of ß-cells, and % of ß-cells per islet which were negatively correlated with MCC. Similarly, there was a negative correlation between MCC with ß-cell proliferation and neogenesis frequency in DM. This highlights the potential association between the increased MC number and the diminished islet`s mass as well as regeneration which may fasten the progression of T2D.

Development, growth and maintenance of ß-cell mass: models are also part of the story.

Pancreatic ß-cells in the islets of Langerhans play a crucial role in regulating glucose homeostasis in the circulation. Loss of ß-cell mass or function due to environmental, genetic and immunological factors leads to the manifestation of diabetes mellitus. The mechanisms regulating the dynamics of pancreatic ß-cell mass during normal development and diabetes progression are complex. To fully unravel such complexity, experimental and clinical approaches need to be combined with mathematical and computational models. In the natural sciences, mathematical and computational models have aided the identification of key mechanisms underlying the behavior of systems comprising multiple interacting components. A number of mathematical and computational models have been proposed to explain the development, growth and death of pancreatic ß-cells. In this review, we discuss some of these models and how their predictions provide novel insight into the mechanisms controlling ß-cell mass during normal development and diabetes progression. Lastly, we discuss a handful of the major open questions in the field.

Islet cell plasticity and regeneration.

Insulin-dependent diabetes is a complex multifactorial disorder characterized by loss or dysfunction of ß-cells resulting in failure of metabolic control. Even though type 1 and 2 diabetes differ in their pathogenesis, restoring ß-cell function is the overarching goal for improved therapy of both diseases. This could be achieved either by cell-replacement therapy or by triggering intrinsic regenerative mechanisms of the pancreas. For type 1 diabetes, a combination of ß-cell replacement and immunosuppressive therapy could be a curative treatment, whereas for type 2 diabetes enhancing endogenous mechanisms of ß-cell regeneration might optimize blood glucose control. This review will briefly summarize recent efforts to allow ß-cell regeneration where the most promising approaches are currently (1) increasing ß-cell self-replication or neogenesis from ductal progenitors and (2) conversion of α-cells into ß-cells.