In Vivo Cell Transformation: Neogenesis of Beta Cells from Pancreatic Ductal Cells

1995 ◽  
Vol 4 (4) ◽  
pp. 371-383 ◽  
Author(s):  
Lawrence Rosenberg
Keyword(s):  
Endocrine Cell ◽  
Islet Cell ◽  
Cell Transformation ◽  
Islet Cells ◽  
Cell Mass ◽  
Postnatal Period ◽  
Islet Neogenesis ◽  
Ductal Cells ◽  
Pancreatic Ductal Cells

During embryogenesis, islet cells differentiate from primitive duct-like cells. This process leads to the formation of islets in the mesenchyme adjacent to the ducts. In the postnatal period, any further expansion of the pancreatic endocrine cell mass will manifest itself either by a limited proliferation of the existing islet cells, or by a reiteration of ontogenetic development. It is the latter, cell transformation by a process of differentiation from a multipotential cell, that will be referred to in this review as islet neogenesis. To better appreciate the mechanisms underlying islet cell neogenesis, some of the basic concepts of developmental biology will be reviewed. Considerable discussion is devoted to the subject of transdifferentiation, a change in a cell or in its progeny from one differentiated phenotype to another, where the change includes both morphological and functional phenotypic markers. While in vitro studies with fetal and neonatal pancreata strongly suggest that new islet tissue is derived from ductal epithelium, what is not established is whether the primary cell is a committed endocrine cell or duct-like cell capable of transdifferentiation. Next, research in the field of β-cell neogenesis is surveyed, in preparation for the examination of whether there is a physiological means of inducing islet cell regeneration, and whether the new islet mass will function in a regulated manner to reverse or stabilize a diabetic state? Our belief is that the pancreas retains the ability to regenerate a functioning islet cell mass in the postnatal period, and that the process of cell transformation leading to islet neogenesis is mediated by growth factors that are intrinsic to the gland. Furthermore, it is our contention that these factors act directly or indirectly on a multipotential cell, probably associated with the ductular epithelium, to induce endocrine cell differentiation. In other words, new islet formation in the postnatal period reiterates the normal ontogeny of islet cell development. These ideas will be fully developed in a discussion of the Partial Duct Obstruction (PDO) Model.

scholarly journals Pancreatic Duct Cells Isolated From Canines Differentiate Into Beta-Like Pancreatic Islet Cells

2022 ◽  
Vol 8 ◽  
Author(s):  
Yuhua Gao ◽  
Weijun Guan ◽  
Chunyu Bai
Keyword(s):  
Pancreatic Islet ◽  
Pancreatic Beta Cells ◽  
Islet Cells ◽  
Pancreatic Islet Cells ◽  
Cell Therapies ◽  
Ductal Cells ◽  
Pancreatic Ductal Cells ◽  
Insulin Granules ◽  
Glucose Stimulated Insulin Secretion

In this study, we isolated and cultured pancreatic ductal cells from canines and revealed the possibility for using them to differentiate into functional pancreatic beta cells in vitro. Passaged pancreatic ductal cells were induced to differentiate into beta-like pancreatic islet cells using a mixture of induced factors. Differentiated pancreatic ductal cells were analyzed based on intracellular insulin granules using transmission electron microscopy, the expression of insulin and glucagon using immunofluorescence, and glucose-stimulated insulin secretion using ELISA. Our data revealed that differentiated pancreatic ductal cells not only expressed insulin and glucagon but also synthesized insulin granules and secreted insulin at different glucose concentrations. Our study might assist in the development of effective cell therapies for the treatment of type 1 diabetes mellitus in dogs.

scholarly journals Analysis of morphological and functional maturation of neoislets generated in vitro from pancreatic ductal cells and their suitability for islet banking and transplantation

2004 ◽  
Vol 182 (1) ◽  
pp. 105-112 ◽  
Author(s):  
MR Katdare ◽  
RR Bhonde ◽  
PB Parab
Keyword(s):  
Insulin Secretion ◽  
Cell Cultures ◽  
Islet Cell ◽  
Ductal Epithelial Cell ◽  
Ductal Cells ◽  
Functional Maturation ◽  
Pancreatic Ductal Cells ◽  
Large Numbers ◽  
Cell Banking

The pancreatic ductal stem cells are known to differentiate into islets of Langerhans; however, their yield is limited and the islet population is not defined. Therefore, the aims of the present study were to improvise a methodology for obtaining large numbers of islets in vitro and to characterize their morphological and functional status for islet cell banking and transplantation. Pancreatic ductal epithelial cell cultures were set in serum-free medium. Monolayers of epithelial cells in culture gave rise to islet-like clusters within 3-4 weeks. The identity of neoislets was confirmed by dithizone staining and analysis of the gene expression for endocrine markers by reverse transcriptase-polymerase chain reaction (RT-PCR). The islet population obtained was analysed by image analysis and insulin secretion in response to secretagogues. The cellular extracts from neoislets were immunoreactive to anti-insulin antibody and expressed insulin, glucagon, GLUT-2, PDX-1 and Reg-1 genes. The islets generated within 3-4 weeks exhibited a mixed population of large- and small-sized islets with clear cut dichotomy in the pattern of their insulin secretion in response to L-arginine and glucose. These neoislets maintained their structural and functional integrity on cryopreservation and transplantation indicating their suitability for islet cell banking. Thus, the present study describes an improved method for obtaining a constant supply of large numbers of islets from pancreatic ductal stem cell cultures. The newly generated islets undergo functional maturation indicating their suitability for transplantation.

EGF receptor in pancreatic β-cell mass regulation

2008 ◽  
Vol 36 (3) ◽  
pp. 280-285 ◽  
Author(s):  
Päivi Miettinen ◽  
Päivi Ormio ◽  
Elina Hakonen ◽  
Meenal Banerjee ◽  
Timo Otonkoski
Keyword(s):  
Egf Receptor ◽  
Islet Cells ◽  
Cell Mass ◽  
In Vitro Models ◽  
Β Cell ◽  
Positive Effects ◽  
Ductal Cells ◽  
Gut Hormone ◽  
Glucagon Like Peptide 1

Pancreatic islet development is impaired in mice lacking EGFRs (epidermal growth factor receptors). Even partial tissue-specific attenuation of EGFR signalling in the islets leads to markedly reduced β-cell proliferation and development of diabetes during the first weeks after birth. Out of the many EGFR ligands, betacellulin has been specifically associated with positive effects on β-cell growth, through both increased proliferation and neogenesis. EGFR action is also necessary for the β-cell mitogenic activity of the gut hormone GLP-1 (glucagon-like peptide 1). Finally, in vitro models demonstrate a central role for EGFR in transdifferentiation of pancreatic acinar and ductal cells into endocrine islet cells. EGFR thus plays an essential role in β-cell mass regulation, but its mechanisms of action remain poorly understood.

scholarly journals A Clinically Applicable Positive Allosteric Modulator of GABA Receptors Promotes Human β-Cell Replication and Survival as well as GABA’s Ability to Inhibit Inflammatory T Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Jide Tian ◽  
Hoa Dang ◽  
Nataliya Karashchuk ◽  
Irvin Xu ◽  
Daniel L. Kaufman
Keyword(s):  
T Cell ◽  
Cell Survival ◽  
Islet Cell ◽  
Cell Mass ◽  
T Cell Responses ◽  
Human Islet ◽  
Cell Replication ◽  
Cell Responses ◽  
Autoreactive T Cell

A major goal of T1D research is to develop new approaches to increase β-cell mass and control autoreactive T cell responses. GABAA-receptors (GABAA-Rs) are promising drug targets in both those regards due to their abilities to promote β-cell replication and survival, as well as inhibit autoreactive T cell responses. We previously showed that positive allosteric modulators (PAMs) of GABAA-Rs could promote rat β-cell line INS-1 and human islet cell replication in vitro. Here, we assessed whether treatment with alprazolam, a widely prescribed GABAA-R PAM, could promote β-cell survival and replication in human islets after implantation into NOD/scid mice. We observed that alprazolam treatment significantly reduced human islet cell apoptosis following transplantation and increased β-cell replication in the xenografts. Evidently, the GABAA-R PAM works in conjunction with GABA secreted from β-cells to increase β-cell survival and replication. Treatment with both the PAM and GABA further enhanced human β-cell replication. Alprazolam also augmented the ability of suboptimal doses of GABA to inhibit antigen-specific T cell responses in vitro. Thus, combined GABAA-R agonist and PAM treatment may help control inflammatory immune responses using reduced drug dosages. Together, these findings suggest that GABAA-R PAMs represent a promising drug class for safely modulating islet cells toward beneficial outcomes to help prevent or reverse T1D and, together with a GABAA-R agonist, may have broader applications for ameliorating other disorders in which inflammation contributes to the disease process.

In vitro lymphocyte recognition of islet cells following in vivo priming with allogeneic murine pancreatic islets

1984 ◽  
Vol 105 (1) ◽  
pp. 87-92 ◽  
Author(s):  
Joanne Scott ◽  
Peter G. MacKay ◽  
Åke Lernmark
Keyword(s):  
Lymph Node ◽  
Pancreatic Islets ◽  
Islet Cell ◽  
Islet Cells ◽  
Culture Conditions ◽  
Pancreatic Tissue ◽  
Insulin Dependent ◽  
Lymph Node Cells

Abstract. Lymphocytes from patients with insulin-dependent diabetes have been shown to be sensitized to pancreatic tissue antigens. Mice immunized with homologous pancreatic islets have been found to develop glucose intolerance and insulitis. Since lymphocytes may be involved in diabetogenesis, we wished to determine if lymph node cells from islet-immunized mice can recognize and respond to islet cells in vitro. A.TL female mice were immunized with an emulsion of BALB/c islet homogenate and complete Freund's adjuvant (CFA); sham-treated A.TL mice were injected with adjuvant and water. Mice were sacrificed 7–8 days later and the draining lymph nodes were removed. The lymph node cells were co-cultured with freshly prepared irradiated BALB/c islet cell, which served as stimulator cells. The co-cultures were incubated for 24–26 h at 37°C, followed by a 16 h [3H]thymidine (TdR) pulse. A significant proliferation of lymph node cells from islet-primed mice was induced during the in vitro stimulation with irradiated islet cells when compared with lymph node cells from sham-treated mice (P < 0.001). The response may be islet-cell-specific, since irradiated lymph node cells from BALB/c mice failed to proliferative response under the same culture conditions (P > 0.80).

An in Vitro Study of Pancreatic Ductal Cells

1978 ◽  
Vol 157 (1) ◽  
pp. 23-28 ◽  
Author(s):  
M. Singh ◽  
N. M. Parks ◽  
P. D. Webster
Keyword(s):  
In Vitro Study ◽  
Vitro Study ◽  
Ductal Cells ◽  
Pancreatic Ductal Cells

Human pancreatic ductal cells express PDX-1 in culture and may contribute to islet neogenesis in clinically transplanted grafts.

2003 ◽  
Vol 76 (Supplement) ◽  
pp. S60
Author(s):  
Cale N. Street ◽  
A. M. James Shapiro ◽  
Jonathan Lakey ◽  
Edmund A. Ryan ◽  
Sharleen Imes ◽  
...  
Keyword(s):  
Islet Neogenesis ◽  
Ductal Cells ◽  
Pancreatic Ductal Cells

scholarly journals Expansion and conversion of human pancreatic ductal cells into insulin-secreting endocrine cells

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Jonghyeob Lee ◽  
Takuya Sugiyama ◽  
Yinghua Liu ◽  
Jing Wang ◽  
Xueying Gu ◽  
...  
Keyword(s):  
Endocrine Cells ◽  
General Strategy ◽  
In Vitro Production ◽  
Β Cell ◽  
Ductal Cells ◽  
Adult Human ◽  
Pancreatic Ductal Cells ◽  
Pancreatic Cells ◽  
Vitro Production

Pancreatic islet β-cell insufficiency underlies pathogenesis of diabetes mellitus; thus, functional β-cell replacement from renewable sources is the focus of intensive worldwide effort. However, in vitro production of progeny that secrete insulin in response to physiological cues from primary human cells has proven elusive. Here we describe fractionation, expansion and conversion of primary adult human pancreatic ductal cells into progeny resembling native β-cells. FACS-sorted adult human ductal cells clonally expanded as spheres in culture, while retaining ductal characteristics. Expression of the cardinal islet developmental regulators Neurog3, MafA, Pdx1 and Pax6 converted exocrine duct cells into endocrine progeny with hallmark β-cell properties, including the ability to synthesize, process and store insulin, and secrete it in response to glucose or other depolarizing stimuli. These studies provide evidence that genetic reprogramming of expandable human pancreatic cells with defined factors may serve as a general strategy for islet replacement in diabetes.

scholarly journals Possible relationship between changes in islet neogenesis and islet neogenesis-associated protein-positive cell mass induced by sucrose administration to normal hamsters

2000 ◽  
Vol 165 (3) ◽  
pp. 725-733 ◽  
Author(s):  
H Del Zotto ◽  
L Massa ◽  
R Rafaeloff ◽  
GL Pittenger ◽  
A Vinik ◽  
...  
Keyword(s):  
Beta Cell ◽  
Endocrine Pancreas ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Serum Glucose ◽  
Islet Neogenesis ◽  
Insulin Levels ◽  
Glucose Levels ◽  
Ductal Cells ◽  
Islet Volume

The possible relationship between changes in islet cell mass and in islet neogenesis-associated protein (INGAP)-cell mass induced by sucrose administration to normal hamsters was investigated. Normal hamsters were given sucrose (10% in drinking water) for 5 (S8) or 21 (S24) weeks and compared with control (C) fed hamsters. Serum glucose and insulin levels were measured and quantitative immunocytochemistry of the endocrine pancreas was performed. Serum glucose levels were comparable among the groups, while insulin levels were higher in S hamsters. There was a significant increase in beta-cell mass (P<0.02) and in beta-cell 5-bromo-2'-deoxyuridine index (P<0.01), and a significant decrease in islet volume (P<0.01) only in S8 vs C8 hamsters. Cytokeratin (CK)-labelled cells were detected only in S8 hamsters. INGAP-positive cell mass was significantly larger only in S8 vs C8 hamsters. Endocrine INGAP-positive cells were located at the islet periphery ( approximately 96%), spread within the exocrine pancreas ( approximately 3%), and in ductal cells (<1%) in all groups. INGAP positivity and glucagon co-localization varied according to topographic location and type of treatment. In C8 hamsters, 49.1+/-6. 9% cells were INGAP- and glucagon-positive in the islets, while this percentage decreased by almost half in endocrine extra-insular and ductal cells. In S8 animals, co-expression increased in endocrine extra-insular cells to 36.3+/-9.5%, with similar figures in the islets, decreasing to 19.7+/-6.9% in ductal cells. INGAP-positive cells located at the islet periphery also co-expressed CK. In conclusion, a significant increase of INGAP-positive cell mass was only observed at 8 weeks when neogenesis was present, suggesting that this peptide might participate in the control of islet neogenesis. Thus, INGAP could be a potentially useful tool to treat conditions in which there is a decrease in beta-cell mass.

Sign in / Sign up

Export Citation Format

Share Document