The stromal cell–derived factor-1α/CXCR4 ligand–receptor axis is critical for progenitor survival and migration in the pancreas

The SDF-1α/CXCR4 ligand/chemokine receptor pair is required for appropriate patterning during ontogeny and stimulates the growth and differentiation of critical cell types. Here, we demonstrate SDF-1α and CXCR4 expression in fetal pancreas. We have found that SDF-1α and its receptor CXCR4 are expressed in islets, also CXCR4 is expressed in and around the proliferating duct epithelium of the regenerating pancreas of the interferon (IFN) γ–nonobese diabetic mouse. We show that SDF-1α stimulates the phosphorylation of Akt, mitogen-activated protein kinase, and Src in pancreatic duct cells. Furthermore, migration assays indicate a stimulatory effect of SDF-1α on ductal cell migration. Importantly, blocking the SDF-1α/CXCR4 axis in IFNγ-nonobese diabetic mice resulted in diminished proliferation and increased apoptosis in the pancreatic ductal cells. Together, these data indicate that the SDF-1α–CXCR4 ligand receptor axis is an obligatory component in the maintenance of duct cell survival, proliferation, and migration during pancreatic regeneration.

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Transdifferentiation of pancreatic ductal cells to endocrine β-cells

Biochemical Society Transactions ◽

10.1042/bst0360353 ◽

2008 ◽

Vol 36 (3) ◽

pp. 353-356 ◽

Cited By ~ 97

Author(s):

Susan Bonner-Weir ◽

Akari Inada ◽

Shigeru Yatoh ◽

Wan-Chun Li ◽

Tandy Aye ◽

...

Keyword(s):

Ex Vivo ◽

Duct Cell ◽

Cell Types ◽

Lineage Tracing ◽

Β Cells ◽

Partial Pancreatectomy ◽

Pancreatic Cell ◽

Ductal Cells ◽

Pancreatic Ductal Cells

The regenerative process in the pancreas is of particular interest, since diabetes, whether Type 1 or Type 2, results from an inadequate amount of insulin-producing β-cells. Islet neogenesis, or the formation of new islets, seen as budding of hormone-positive cells from the ductal epithelium, has long been considered to be one of the mechanisms of normal islet growth after birth and in regeneration, and suggested the presence of pancreatic stem cells. Results from the rat regeneration model of partial pancreatectomy led us to hypothesize that differentiated pancreatic ductal cells were the pancreatic progenitors after birth, and that with replication they regressed to a less differentiated phenotype and then could differentiate to form new acini and islets. There are numerous supportive results for this hypothesis of neogenesis, including the ability of purified primary human ducts to form insulin-positive cells budding from ducts. However, to rigorously test this hypothesis, we took a direct approach of genetically marking ductal cells using CAII (carbonic anhydrase II) as a duct-cell-specific promoter to drive Cre recombinase in lineage-tracing experiments using the Cre-Lox system. We show that CAII-expressing pancreatic cells act as progenitors that give rise to both new islets and acini after birth and after injury (ductal ligation). This identification of a differentiated pancreatic cell type as an in vivo progenitor for all differentiated pancreatic cell types has implications for a potential expandable source for new islets for replenishment therapy for diabetes either in vivo or ex vivo.

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RAT PANCREATIC DUCTAL CELLS (PDC) PURIFIED BY AN IMMUNOISOLATION TECHNIQUE MAINTAIN EXPRESSION OF ANTIGENIC DUCT CELL-SPECIFIC MARKERS IN LONG-TERM CULTURE

Journal of Pediatric Gastroenterology and Nutrition ◽

10.1097/00005176-199510000-00121 ◽

1995 ◽

Vol 21 (3) ◽

pp. 351

Author(s):

L. B. Shalon ◽

T. A. Konkin ◽

R. A. Faris

Keyword(s):

Duct Cell ◽

Long Term Culture ◽

Ductal Cells ◽

Pancreatic Ductal Cells

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Imaging the emergence and natural progression of spontaneous autoimmune diabetes

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1707381114 ◽

2017 ◽

Vol 114 (37) ◽

pp. E7776-E7785 ◽

Cited By ~ 19

Author(s):

James F. Mohan ◽

Rainer H. Kohler ◽

Jonathan A. Hill ◽

Ralph Weissleder ◽

Diane Mathis ◽

...

Keyword(s):

T Cells ◽

Autoimmune Diabetes ◽

Cell Mass ◽

Cell Types ◽

Diabetic Mouse ◽

T Cell Infiltration ◽

Nonobese Diabetic ◽

Reporter Mice ◽

Natural Progression ◽

Restricted Mobility

Type 1 diabetes in the nonobese diabetic mouse stems from an infiltration of the pancreatic islets by a mixed population of immunocytes, which results in the impairment and eventual destruction of insulin-producing β-cells. Little is known about the dynamics of lymphocyte movement in the pancreas during disease progression. Using advanced intravital imaging approaches and newly created reporter mice (Flt3-BFP2, Mertk-GFP-DTR, Cd4-tdTomato, Cd8a-tdTomato), we show that the autoimmune process initiates first with a T cell infiltration into the islets, where they have restricted mobility but reside and are activated in apposition to CX3CR1+ macrophages. The main expansion then occurs in the connective tissue outside the islet, which remains more or less intact. CD4+ and CD8+ T cells, Tregs, and dendritic cells (DCs) are highly mobile, going along microvascular tracks, while static macrophages (MF) form a more rigid structure, often encasing the islet cell mass. Transient cell–cell interactions are formed between T cells and both MFs and DCs, but also surprisingly between MFs and DCs themselves, possibly denoting antigen transfer. In later stages, extensive islet destruction coincides with preferential antigen presentation to, and activation of, CD8+ T cells. Throughout the process, Tregs patrol the active compartments, consistent with the notion that they control the activation of many cell types.

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The specific p38 mitogen-activated protein kinase pathway inhibitor FR167653 keeps insulitis benign in nonobese diabetic mice

Life Sciences ◽

10.1016/j.lfs.2003.09.045 ◽

2004 ◽

Vol 74 (14) ◽

pp. 1817-1827 ◽

Cited By ~ 15

Author(s):

Hitoshi Ando ◽

Seiichiro Kurita ◽

Toshinari Takamura

Keyword(s):

Protein Kinase ◽

Mitogen Activated Protein Kinase ◽

Diabetic Mice ◽

Nonobese Diabetic ◽

Mitogen Activated Protein ◽

Nonobese Diabetic Mice ◽

Kinase Pathway

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Production of interleukin 10 by islet cells accelerates immune-mediated destruction of beta cells in nonobese diabetic mice.

Journal of Experimental Medicine ◽

10.1084/jem.179.4.1379 ◽

1994 ◽

Vol 179 (4) ◽

pp. 1379-1384 ◽

Cited By ~ 214

Author(s):

L Wogensen ◽

M S Lee ◽

N Sarvetnick

Keyword(s):

Islet Cells ◽

Autoimmune Diabetes ◽

Nod Mice ◽

Insulin Dependent Diabetes Mellitus ◽

Interleukin 10 ◽

Diabetic Mouse ◽

Dependent Diabetes Mellitus ◽

Beta Cell Destruction ◽

Nonobese Diabetic ◽

Nonobese Diabetic Mice

The T helper type 2 (Th2) cell product interleukin 10 (IL-10) inhibits the proliferation and function of Th1 lymphocytes and macrophages (M phi). The nonobese diabetic mouse strain (NOD/Shi) develops a M phi and T cell-dependent autoimmune diabetes that closely resembles human insulin-dependent diabetes mellitus (IDDM). The objective of the present study was to explore the consequences of localized production of IL-10 on diabetes development in NOD/Shi mice. Surprisingly, local production of IL-10 accelerated the onset and increased the prevalence of diabetes, since diabetes developed at 5-10 wk of age in 92% of IL-10 positive I-A beta g7/g7, I-E- mice in first (N2) and second (N3) generation backcrosses between IL-10 transgenic BALB/c mice and (NOD/Shi) mice. None of the IL-10 negative major histocompatibility complex-identical littermates were diabetic at this age. Furthermore, diabetes developed in 33% of I-A beta g7/d, I-E+ N3 mice in the presence of IL-10 before the mice were 10 wk old. Our findings support the notion that IL-10 should not simply be regarded as an immunoinhibitory cytokine, since it possesses powerful, immunostimulatory properties as well. Furthermore, our observations suggest that beta cell destruction in NOD mice may be a Th2-mediated event.

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Preventive and Therapeutic Potential of p38α-Selective Mitogen-Activated Protein Kinase Inhibitor in Nonobese Diabetic Mice with Type 1 Diabetes

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.105.097857 ◽

2006 ◽

Vol 318 (1) ◽

pp. 99-107 ◽

Cited By ~ 6

Author(s):

Satyanarayana Medicherla ◽

Andrew A. Protter ◽

Jing Ying Ma ◽

Ruban Mangadu ◽

Ramona Almirez ◽

...

Keyword(s):

Type 1 Diabetes ◽

Protein Kinase ◽

Kinase Inhibitor ◽

Therapeutic Potential ◽

Mitogen Activated Protein Kinase ◽

Diabetic Mice ◽

Nonobese Diabetic ◽

Mitogen Activated Protein ◽

Nonobese Diabetic Mice

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The influence of parathyroid hormone 1-34 on the osteogenic characteristics of adipose- and bone-marrow-derived mesenchymal stem cells from juvenile and ovarectomized rats

Bone and Joint Research ◽

10.1302/2046-3758.88.bjr-2019-0018.r1 ◽

2019 ◽

Vol 8 (8) ◽

pp. 397-404 ◽

Cited By ~ 3

Author(s):

Liza Osagie-Clouard ◽

Anita Sanghani-Kerai ◽

Melanie Coathup ◽

Richard Meeson ◽

Timothy Briggs ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Parathyroid Hormone ◽

Adipogenic Differentiation ◽

Cell Types ◽

Osteogenic Potential ◽

Ovx Rats ◽

Stromal Cell Derived Factor ◽

And Migration

Objectives Mesenchymal stem cells (MSCs) are of growing interest in terms of bone regeneration. Most preclinical trials utilize bone-marrow-derived mesenchymal stem cells (bMSCs), although this is not without isolation and expansion difficulties. The aim of this study was: to compare the characteristics of bMSCs and adipose-derived mesenchymal stem cells (AdMSCs) from juvenile, adult, and ovarectomized (OVX) rats; and to assess the effect of human parathyroid hormone (hPTH) 1-34 on their osteogenic potential and migration to stromal cell-derived factor-1 (SDF-1). Methods Cells were isolated from the adipose and bone marrow of juvenile, adult, and previously OVX Wistar rats, and were characterized with flow cytometry, proliferation assays, osteogenic and adipogenic differentiation, and migration to SDF-1. Experiments were repeated with and without intermittent hPTH 1-34. Results Juvenile and adult MSCs demonstrated significantly increased osteogenic and adipogenic differentiation and superior migration towards SDF-1 compared with OVX groups; this was the case for AdMSCs and bMSCs equally. Parathyroid hormone (PTH) increased parameters of osteogenic differentiation and migration to SDF-1. This was significant for all cell types, although it had the most significant effect on cells derived from OVX animals. bMSCs from all groups showed increased mineralization and migration to SDF-1 compared with AdMSCs. Conclusion Juvenile MSCs showed significantly greater migration to SDF-1 and significantly greater osteogenic and adipogenic differentiation compared with cells from osteopenic rats; this was true for bMSCs and AdMSCs. The addition of PTH increased these characteristics, with the most significant effect on cells derived from OVX animals, further illustrating possible clinical application of both PTH and MSCs in bone regenerative therapies. Cite this article:L. Osagie-Clouard, A. Sanghani-Kerai, M. Coathup, R. Meeson, T. Briggs, G. Blunn. The influence of parathyroid hormone 1-34 on the osteogenic characteristics of adipose- and bone-marrow-derived mesenchymal stem cells from juvenile and ovarectomized rats. Bone Joint Res 2019;8:397–404. DOI: 10.1302/2046-3758.88.BJR-2019-0018.R1.

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Proteomic Investigation of Glyceraldehyde-Derived Intracellular AGEs and Their Potential Influence on Pancreatic Ductal Cells

Cells ◽

10.3390/cells10051005 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1005

Author(s):

Lakmini Senavirathna ◽

Cheng Ma ◽

Ru Chen ◽

Sheng Pan

Keyword(s):

Oxidative Stress ◽

Cancer Cells ◽

Cancer Progression ◽

S100 Protein ◽

Cell Types ◽

Functional Studies ◽

Ductal Cells ◽

Pancreatic Ductal Cells ◽

Pancreatic Cancer Cells ◽

Glycated Proteins

Glyceraldehyde-derived advanced glycation end products (AGEs) play an important role in the pathogenesis of many diseases including cancer. Accumulation of intracellular AGEs could stimulate cancer induction and facilitate cancer progression. We evaluated the toxic effect of glyceraldehyde-derived intracellular AGEs on normal and malignant pancreatic ductal cells by assessing the cell viability, toxicity, and oxidative stress, followed by proteomic analysis. Our functional studies showed that pancreatic cancer cells (PANC-1 and MIA PaCa-2) were more resistant to glyceraldehyde treatment compared to normal pancreatic ductal epithelial cells (HPDE), while cytotoxicity effects were observed in all cell types. Furthermore, using 13C isotopic labeled glyceraldehyde, the proteomic data revealed a dose-dependent increment of the number of glycation adducts in both these cell types. HPDE cells showed a higher number of intracellular AGEs compared to cancer cells. At a molecular level, the glycations in the lysine residues of proteins showed a concurrent increase with the concentration of the glyceraldehyde treatment, while the arginine glycations appeared to be less affected by the glyceraldehyde doses. Further pathway analysis of these glycated proteins suggested that the glycated proteins participate in important biological processes that are major hallmarks of cancer initiation and progression, including metabolic processes, immune response, oxidative stress, apoptosis, and S100 protein binding.

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