scholarly journals β-Cell Generation: Can Rodent Studies Be Translated to Humans?

2011 ◽  
Vol 2011 ◽  
pp. 1-15 ◽  
Author(s):  
Françoise Carlotti ◽  
Arnaud Zaldumbide ◽  
Johanne H. Ellenbroek ◽  
H. Siebe Spijker ◽  
Rob C. Hoeben ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Cell Mass ◽  
Cell Types ◽  
Organ Donors ◽  
Cell Replacement Therapy ◽  
Β Cell ◽  
Cell Replacement ◽  
Therapeutic Alternatives

β-cell replacement by allogeneic islet transplantation is a promising approach for patients with type 1 diabetes, but the shortage of organ donors requires new sources ofβcells. Islet regenerationin vivoand generation ofβ-cellsex vivofollowed by transplantation represent attractive therapeutic alternatives to restore theβ-cell mass. In this paper, we discuss different postnatal cell types that have been envisaged as potential sources for futureβ-cell replacement therapy. The ultimate goal being translation to the clinic, a particular attention is given to the discrepancies between findings from studies performed in rodents (bothex vivoon primary cells andin vivoon animal models), when compared with clinical data and studies performed on human cells.

Cellular plasticity of the pancreas

2009 ◽  
Vol 390 (10) ◽  
Author(s):  
Luc Baeyens ◽  
Luc Bouwens
Keyword(s):  
Diabetes Mellitus ◽  
Cell Differentiation ◽  
Cell Types ◽  
Β Cells ◽  
Cell Replacement Therapy ◽  
Β Cell ◽  
Pancreatic Cell ◽  
Cell Replacement

Abstract Cell replacement therapy holds promises for treatment of patients suffering from diabetes mellitus. When determining the appropriate strategies to amplify the amount of transplantable β-cells, sufficient knowledge of the developmental programs regulating β-cell differentiation is crucial. Here, we describe the plasticity of the different pancreatic cell types in vivo and in vitro and their potential to serve as β-cell progenitor.

Harnessing immune cells to enhance β-cell mass in type 1 diabetes

2016 ◽  
Vol 64 (1) ◽  
pp. 14-20 ◽  
Author(s):  
Ercument Dirice ◽  
Rohit N Kulkarni
Keyword(s):  
Type 1 Diabetes ◽  
Mononuclear Cells ◽  
Islet Cells ◽  
Cell Mass ◽  
Cell Loss ◽  
Cell Types ◽  
Β Cells ◽  
Β Cell ◽  
Autoimmune Attack

Type 1 diabetes is characterized by early β-cell loss leading to insulin dependence in virtually all patients with the disease in order to maintain glucose homeostasis. Most studies over the past few decades have focused on limiting the autoimmune attack on the β cells. However, emerging data from patients with long-standing diabetes who continue to harbor functional insulin-producing cells in their diseased pancreas have prompted scientists to examine whether proliferation of existing β cells can be enhanced to promote better glycemic control. In support of this concept, several studies indicate that mononuclear cells that infiltrate the islets have the capacity to trigger proliferation of islet cells including β cells. These observations indicate the exciting possibility of identifying those mononuclear cell types and their soluble factors and harnessing their ability to promote β-cell growth concomitant with autoimmune therapy to prevent the onset and/or halt the progression of the disease.

scholarly journals Tumorigenicity of pluripotent stem cells: biological insights from molecular imaging

2010 ◽  
Vol 7 (suppl_6) ◽  
Author(s):  
Nigel G. Kooreman ◽  
Joseph C. Wu
Keyword(s):  
Stem Cells ◽  
Molecular Imaging ◽  
Pluripotent Stem Cells ◽  
Embryonic Stem ◽  
Cell Types ◽  
Cell Replacement Therapy ◽  
Cell Replacement ◽  
Induced Pluripotent ◽  
Teratoma Formation

Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have the ability (i) to duplicate indefinitely while maintaining pluripotency and (ii) to differentiate into cell types of all three embryonic germ layers. These two properties of ESCs and iPSCs make them potentially suitable for tissue engineering and cell replacement therapy for many different diseases, including Parkinson's disease, diabetes and heart disease. However, one critical obstacle in the clinical application of ESCs or iPSCs is the risk of teratoma formation. The emerging field of molecular imaging is allowing researchers to track transplanted ESCs or iPSCs in vivo , enabling early detection of teratomas.

scholarly journals β-cell Mass in Nondiabetic Autoantibody-Positive Subjects: An Analysis Based on the Network for Pancreatic Organ Donors Database

2016 ◽  
Vol 101 (4) ◽  
pp. 1390-1397 ◽  
Author(s):  
Marc Diedisheim ◽  
Roberto Mallone ◽  
Christian Boitard ◽  
Etienne Larger
Keyword(s):  
Cell Mass ◽  
Organ Donors ◽  
Cell Area ◽  
Β Cell ◽  
Future Studies ◽  
Recent Onset ◽  
Quantification Method ◽  
Virtual Slides ◽  
Automated Quantification

Abstract Context: Little information is available about β-cell mass in antibody-positive (Ab+) nondiabetic subjects. Objective: We have investigated whether the publicly available virtual slides of the Network for Pancreatic Organ Donors with Diabetes (nPOD) project can be used to assess β-cell mass and distribution in nondiabetic antibody-negative (Ab−) and antibody-positive (Ab+) subjects and in patients with recent-onset type 1 diabetes (T1D). Subjects and Methods: We developed a semi-automated quantification method and applied it to 415 insulin-stained slides from 69 Ab− subjects, 101 slides from 18 Ab+ subjects, and 46 slides from eight recent-onset (<3 y) T1D subjects. Among these subjects, 48, 17, and seven had an available pancreatic mass, respectively, and were used for the quantification of β-cell mass. Results: In Ab− subjects, the β-cell and endocrine mass were 0.66 ± 0.42 and 1.0 ± 0.65 g, respectively. Nonexocrine tissue represented 29% of pancreatic area, a proportion that increased with age. Proportional β-cell area relative to total pancreatic area was higher in the tail compared with head (0.83 vs 0.71%; P < .001). In Ab+ subjects, β-cell mass and β-cell area were similar to those of Ab− individuals, whereas these parameters were dramatically decreased in recent-onset T1D patients. Conclusion: The virtual slides of the nPOD project can be used for quantification projects. In Ab+ nondiabetic subjects, the β-cell mass was not decreased. However, as this cohort is largely composed of donors from the general population, with a single autoantibody, future studies with a larger number of donors with multiple autoantibodies and predisposing human leucocyte antigen genes are required to better define the dynamics of β-cell destruction in the preclinical phases of T1D.

scholarly journals Exocytosis Protein DOC2B as a Biomarker of Type 1 Diabetes

2018 ◽  
Vol 103 (5) ◽  
pp. 1966-1976 ◽  
Author(s):  
Arianne Aslamy ◽  
Eunjin Oh ◽  
Miwon Ahn ◽  
Abu Saleh Md Moin ◽  
Mariann Chang ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Islet Transplantation ◽  
Ex Vivo ◽  
Human Subjects ◽  
Cell Mass ◽  
Nod Mice ◽  
Human Islets ◽  
Β Cell ◽  
New Onset

Abstract Context Efforts to preserve β-cell mass in the preclinical stages of type 1 diabetes (T1D) are limited by few blood-derived biomarkers of β-cell destruction. Objective Platelets are proposed sources of blood-derived biomarkers for a variety of diseases, and they show distinct proteomic changes in T1D. Thus, we investigated changes in the exocytosis protein, double C2 domain protein-β (DOC2B) in platelets and islets from T1D humans, and prediabetic nonobese diabetic (NOD) mice. Design, Patients, and Main Outcome Measure Protein levels of DOC2B were assessed in platelets and islets from prediabetic NOD mice and humans, with and without T1D. Seventeen new-onset T1D human subjects (10.3 ± 3.8 years) were recruited immediately following diagnosis, and platelet DOC2B levels were compared with 14 matched nondiabetic subjects (11.4 ± 2.9 years). Furthermore, DOC2B levels were assessed in T1D human pancreatic tissue samples, cytokine-stimulated human islets ex vivo, and platelets from T1D subjects before and after islet transplantation. Results DOC2B protein abundance was substantially reduced in prediabetic NOD mouse platelets, and these changes were mirrored in the pancreatic islets from the same mice. Likewise, human DOC2B levels were reduced over twofold in platelets from new-onset T1D human subjects, and this reduction was mirrored in T1D human islets. Cytokine stimulation of normal islets reduced DOC2B expression ex vivo. Remarkably, platelet DOC2B levels increased after islet transplantation in patients with T1D. Conclusions Reduction of DOC2B is an early feature of T1D, and DOC2B abundance may serve as a valuable in vivo indicator of β-cell mass and an early biomarker of T1D.

PANC-1 Migration and Cluster Formation is Regulated by Short Range Mechanical Forces

2011 ◽  
Author(s):  
Steven Holfinger ◽  
Rashmeet Reen ◽  
William Ackerman ◽  
Douglas Kniss ◽  
Keith J. Gooch
Keyword(s):  
Cluster Formation ◽  
Cell Types ◽  
Organ Donors ◽  
Islet Cell Transplantation ◽  
Insulin Independence ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Levels ◽  
Alternative Sources

Islet cell transplantation has already shown improved control of glucose levels and the potential to achieve insulin independence in type 1 diabetes mellitus, however there is a shortage of organ donors needed to match patient needs [1–2]. In the search for alternative sources of islets, many cell types have shown signs of β-cell differentiation by secreting c-peptide, insulin, and glucagon [3–5]. When maintained in serum-free medium, human epithelial-like pancreatic adenocarcinoma (PANC-1) cells and human-islet derived precursor cells (hIPCs) can go through a morphological transition and cluster [6]. These islet-like cell aggregates subsequently express glucagon, somatostatin, and insulin, indicating that clustering may play an important role in differentiation towards β-cells [7].

scholarly journals β-Cell Maturation and Identity in Health and Disease

2019 ◽  
Vol 20 (21) ◽  
pp. 5417 ◽  
Author(s):  
Salinno ◽  
Cota ◽  
Bastidas-Ponce ◽  
Tarquis-Medina ◽  
Lickert ◽  
...  
Keyword(s):  
Cell Mass ◽  
Β Cells ◽  
Β Cell ◽  
Postnatal Maturation ◽  
Cell Replacement ◽  
Patients With Diabetes ◽  
Health And Disease ◽  
Novel Therapeutic Strategies

The exponential increase of patients with diabetes mellitus urges for novel therapeutic strategies to reduce the socioeconomic burden of this disease. The loss or dysfunction of insulin-producing β-cells, in patients with type 1 and type 2 diabetes respectively, put these cells at the center of the disease initiation and progression. Therefore, major efforts have been taken to restore the β-cell mass by cell-replacement or regeneration approaches. Implementing novel therapies requires deciphering the developmental mechanisms that generate β-cells and determine the acquisition of their physiological phenotype. In this review, we summarize the current understanding of the mechanisms that coordinate the postnatal maturation of β-cells and define their functional identity. Furthermore, we discuss different routes by which β-cells lose their features and functionality in type 1 and 2 diabetic conditions. We then focus on potential mechanisms to restore the functionality of those β-cell populations that have lost their functional phenotype. Finally, we discuss the recent progress and remaining challenges facing the generation of functional mature β-cells from stem cells for cell-replacement therapy for diabetes treatment.

scholarly journals Exocrine pancreas proteases regulate β-cell proliferation in zebrafish ciliopathy models and in murine systems

Biology Open ◽  
2021 ◽  
Vol 10 (6) ◽  
Author(s):  
Timothy L. Hostelley ◽  
Jessica E. Nesmith ◽  
Emily Larkin ◽  
Amanda Jones ◽  
Daniel Boyes ◽  
...  
Keyword(s):  
Exocrine Pancreas ◽  
Ex Vivo ◽  
Cell Mass ◽  
Transgenic Zebrafish ◽  
Genetic Syndromes ◽  
Β Cells ◽  
Β Cell ◽  
Cell Numbers ◽  
Pancreatic Proteases

ABSTRACT Pancreatic β-cells are a critical cell type in the pathology of diabetes. Models of genetic syndromes featuring diabetes can provide novel mechanistic insights into regulation of β-cells in the context of disease. We previously examined β-cell mass in models of two ciliopathies, Alström Syndrome (AS) and Bardet-Biedl Syndrome (BBS), which are similar in the presence of metabolic phenotypes, including obesity, but exhibit strikingly different rates of diabetes. Zebrafish models of these disorders show deficient β-cells with diabetes in AS models and an increased β-cells absent diabetes in BBS models, indicating β-cell generation or maintenance that correlates with disease prevalence. Using transcriptome analyses, differential expression of several exocrine pancreas proteases with directionality that was consistent with β-cell numbers were identified. Based on these lines of evidence, we hypothesized that pancreatic proteases directly impact β-cells. In the present study, we examined this possibility and found that pancreatic protease genes contribute to proper maintenance of normal β-cell numbers, proliferation in larval zebrafish, and regulation of AS and BBS β-cell phenotypes. Our data suggest that these proteins can be taken up directly by cultured β-cells and ex vivo murine islets, inducing proliferation in both. Endogenous uptake of pancreatic proteases by β-cells was confirmed in vivo using transgenic zebrafish and in intact murine pancreata. Taken together, these findings support a novel proliferative signaling role for exocrine pancreas proteases through interaction with endocrine β-cells.

scholarly journals Neratinib protects pancreatic beta cells in diabetes

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Amin Ardestani ◽  
Sijia Li ◽  
Karthika Annamalai ◽  
Blaz Lupse ◽  
Shirin Geravandi ◽  
...  
Keyword(s):  
Pancreatic Beta Cells ◽  
Cell Function ◽  
Cell Mass ◽  
Human Islets ◽  
Β Cells ◽  
Β Cell

Abstract The loss of functional insulin-producing β-cells is a hallmark of diabetes. Mammalian sterile 20-like kinase 1 (MST1) is a key regulator of pancreatic β-cell death and dysfunction; its deficiency restores functional β-cells and normoglycemia. The identification of MST1 inhibitors represents a promising approach for a β-cell-protective diabetes therapy. Here, we identify neratinib, an FDA-approved drug targeting HER2/EGFR dual kinases, as a potent MST1 inhibitor, which improves β-cell survival under multiple diabetogenic conditions in human islets and INS-1E cells. In a pre-clinical study, neratinib attenuates hyperglycemia and improves β-cell function, survival and β-cell mass in type 1 (streptozotocin) and type 2 (obese Leprdb/db) diabetic mouse models. In summary, neratinib is a previously unrecognized inhibitor of MST1 and represents a potential β-cell-protective drug with proof-of-concept in vitro in human islets and in vivo in rodent models of both type 1 and type 2 diabetes.

scholarly journals Antigen-specific immunotherapy combined with a regenerative drug in the treatment of experimental type 1 diabetes

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Adrian Villalba ◽  
Silvia Rodriguez-Fernandez ◽  
David Perna-Barrull ◽  
Rosa-Maria Ampudia ◽  
Laia Gomez-Muñoz ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Mononuclear Cells ◽  
Combined Therapy ◽  
Cell Mass ◽  
Β Cell ◽  
Membrane Expression ◽  
Peripheral Blood Mononuclear ◽  
Autoimmune Attack

Abstract Type 1 diabetes is an autoimmune disease caused by the destruction of the insulin-producing β-cells. To revert type 1 diabetes, the suppression of the autoimmune attack should be combined with a β-cell replacement strategy. It has been previously demonstrated that liraglutide, a glucagon-like peptide-1 receptor agonist, restores β-cell mass in type 1 diabetes, via α-cell transdifferentiation and neogenesis. We report here that treatment with liraglutide does not prevent type 1 diabetes in the spontaneous non-obese diabetic (NOD) mouse model, but it tends to reduce leukocytic islet infiltration. However, in combination with an immunotherapy based on tolerogenic liposomes, it is effective in ameliorating hyperglycaemia in diabetic NOD mice. Importantly, liraglutide is not detrimental for the tolerogenic effect that liposomes exert on dendritic cells from patients with type 1 diabetes in terms of membrane expression of molecules involved in antigen presentation, immunoregulation and activation. Moreover, the in vivo effect of the combined therapy was tested in mice humanised with peripheral blood mononuclear cells from patients with type 1 diabetes, showing no adverse effects in leukocyte subsets. In conclusion, the combination therapy with liraglutide and a liposome-based immunotherapy is a promising candidate strategy for type 1 diabetes.

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