scholarly journals Evidence of Primary  -Cell Destruction by T-Cells and  -Cell Differentiation From Pancreatic Ductal Cells in Diabetes Associated With Active Autoimmune Chronic Pancreatitis

Diabetes Care ◽  
2001 ◽  
Vol 24 (9) ◽  
pp. 1661-1667 ◽  
Author(s):  
S. Tanaka ◽  
T. Kobayashi ◽  
K. Nakanishi ◽  
M. Okubo ◽  
T. Murase ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Pancreatitis ◽  
Cell Differentiation ◽  
Primary Cell ◽  
Ductal Cells ◽  
Cell Destruction ◽  
Pancreatic Ductal Cells

Ductal Cell Reprogramming to Insulin-Producing Beta-Like Cells as a Potential Beta Cell Replacement Source for Chronic Pancreatitis

2019 ◽  
Vol 14 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Aravinth P. Jawahar ◽  
Siddharth Narayanan ◽  
Gopalakrishnan Loganathan ◽  
Jithu Pradeep ◽  
Gary C. Vitale ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Beta Cell ◽  
Lineage Tracing ◽  
Clinical Tool ◽  
Glucose Levels ◽  
Ductal Cells ◽  
Pancreatic Ductal Cells ◽  
Insulin Producing Cells ◽  
Ductal Cell ◽  
Recent Advances

Islet cell auto-transplantation is a novel strategy for maintaining blood glucose levels and improving the quality of life in patients with chronic pancreatitis (CP). Despite the many recent advances associated with this therapy, obtaining a good yield of islet infusate still remains a pressing challenge. Reprogramming technology, by making use of the pancreatic exocrine compartment, can open the possibility of generating novel insulin-producing cells. Several lineage-tracing studies present evidence that exocrine cells undergo dedifferentiation into a progenitor-like state from which they can be manipulated to form insulin-producing cells. This review will present an overview of recent reports that demonstrate the potential of utilizing pancreatic ductal cells (PDCs) for reprogramming into insulin- producing cells, focusing on the recent advances and the conflicting views. A large pool of ductal cells is released along with islets during the human islet isolation process, but these cells are separated from the pure islets during the purification process. By identifying and improving existing ductal cell culture methods and developing a better understanding of mechanisms by which these cells can be manipulated to form hormone-producing islet-like cells, PDCs could prove to be a strong clinical tool in providing an alternative beta cell source, thus helping CP patients maintain their long-term glucose levels.

Chromosomal instability in pancreatic ductal cells from patients with chronic pancreatitis and pancreatic adenocarcinoma

2003 ◽  
Vol 37 (2) ◽  
pp. 201-206 ◽  
Author(s):  
Alexander H. Moskovitz ◽  
Nancy J. Linford ◽  
Teresa A. Brentnall ◽  
Mary P. Bronner ◽  
Barry E. Storer ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Pancreatic Adenocarcinoma ◽  
Chromosomal Instability ◽  
Ductal Cells ◽  
Pancreatic Ductal Cells

scholarly journals Distribution of Indian hedgehog and its receptors patched and smoothened in human chronic pancreatitis

2003 ◽  
Vol 178 (3) ◽  
pp. 467-478 ◽  
Author(s):  
H Kayed ◽  
J Kleeff ◽  
S Keleg ◽  
MW Buchler ◽  
H Friess
Keyword(s):  
Chronic Pancreatitis ◽  
Hedgehog Signaling ◽  
Clinicopathological Parameters ◽  
Indian Hedgehog ◽  
Human Pancreas ◽  
Normal Pancreas ◽  
Ductal Cells ◽  
Pancreatic Ductal Cells ◽  
Normal Human ◽  
Stimulation Of

Indian hedgehog (IHH) and its receptors patched (PTC) and smoothened (SMO) belong to the hedgehog family of signaling molecules, which are essential for a variety of patterning events during mammalian tIssue development. IHH plays a role in pancreas organogenesis and differentiation, as well as in the regulation of insulin production. In the present study, the expression of IHH and its receptors was analyzed in normal human pancreatic and chronic pancreatitis (CP) tIssues using Northern blotting, immunohistochemistry and Western blotting, and was correlated with clinicopathological parameters. In addition, the effects of inhibition and stimulation of the hedgehog signaling pathway on cell growth were determined in TAKA-1 normal pancreatic ductal cells. IHH mRNA was expressed in the normal human pancreas and CP tIssues, with slightly higher expression levels in CP. Using immunohistochemistry, IHH and its receptors were localized mainly in the islet cells of the normal pancreas. In CP, IHH and its receptors were present in the cells forming tubular complexes and in the islets with a different signal pattern compared with the islets in the normal pancreas. Correlation between diabetic and non-diabetic CP patients revealed no significant difference in IHH, SMO, or PTC immunoreactivity. Inhibition of hedgehog signaling in TAKA-1 pancreatic ductal cells using cyclopamine significantly reduced their growth through cell cycle arrest, while stimulation of the IHH pathway enhanced the growth of these cells. In conclusion, IHH and its receptors are expressed in the normal human pancreas and in CP, yet with a different distribution and cellular localization. IHH signaling may be involved in the pathogenesis of CP, i.e. in the formation and proliferation of tubular complexes and in islet cell dysfunction.

scholarly journals Chronic pancreatitis and lipomatosis are associated with defective function of ciliary genes in pancreatic ductal cells

2016 ◽  
pp. ddw332 ◽  
Author(s):  
Cécile Augereau ◽  
Louis Collet ◽  
Pierfrancesco Vargiu ◽  
Carmen Guerra ◽  
Sagrario Ortega ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Ductal Cells ◽  
Pancreatic Ductal Cells

scholarly journals METTL3-dependent m6A modification programs T follicular helper cell differentiation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yingpeng Yao ◽  
Ying Yang ◽  
Wenhui Guo ◽  
Lifan Xu ◽  
Menghao You ◽  
...  
Keyword(s):  
T Cells ◽  
Transcriptional Regulation ◽  
Cell Differentiation ◽  
Ectopic Expression ◽  
Signature Genes ◽  
Follicular Helper ◽  
Conditional Deletion ◽  
A Cell ◽  
A Site ◽  
Post Transcriptional Regulation

AbstractT follicular helper (TFH) cells are specialized effector CD4+ T cells critical to humoral immunity. Whether post-transcriptional regulation has a function in TFH cells is unknown. Here, we show conditional deletion of METTL3 (a methyltransferase catalyzing mRNA N6-methyladenosine (m6A) modification) in CD4+ T cells impairs TFH differentiation and germinal center responses in a cell-intrinsic manner in mice. METTL3 is necessary for expression of important TFH signature genes, including Tcf7, Bcl6, Icos and Cxcr5 and these effects depend on intact methyltransferase activity. m6A-miCLIP-seq shows the 3′ UTR of Tcf7 mRNA is subjected to METTL3-dependent m6A modification. Loss of METTL3 or mutation of the Tcf7 3′ UTR m6A site results in accelerated decay of Tcf7 transcripts. Importantly, ectopic expression of TCF-1 (encoded by Tcf7) rectifies TFH defects owing to METTL3 deficiency. Our findings indicate that METTL3 stabilizes Tcf7 transcripts via m6A modification to ensure activation of a TFH transcriptional program, indicating a pivotal function of post-transcriptional regulation in promoting TFH cell differentiation.

158 Inhibition of PI3Kδ improves tumor specific T cell immunity and metabolic fitness

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A172-A172
Author(s):  
Guillermo Rangel Rivera ◽  
Guillermo Rangel RIvera ◽  
Connor Dwyer ◽  
Dimitrios Arhontoulis ◽  
Hannah Knochelmann ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cell Therapy ◽  
Tumor Immunity ◽  
Mitochondrial Function ◽  
T Cell Differentiation ◽  
Tumor Control ◽  
T Cell Therapy

BackgroundDurable responses have been observed with adoptive T cell therapy (ACT) in some patients. However, current protocols used to expand T cells often exhibit suboptimal tumor control. Failure in these therapies has been attributed to premature differentiation and impaired metabolism of the infused T cells. Previous work done in our lab showed that reduced PI3Kδ signaling improved ACT. Because PI3Kγ and PI3Kδ have critical regulatory roles in T cell differentiation and function, we tested whether inhibiting PI3Kγ could recapitulate or synergize PI3Kδ blockade.MethodsTo test this, we primed melanoma specific CD8+ pmel-1 T cells, which are specific to the glycoprotein 100 epitope, in the presence of PI3Kγ (IPI-459), PI3Kδ (CAL101 or TGR-1202) or PI3Kγ/δ (IPI-145) inhibitors following antigen stimulation with hgp100, and then infused them into 5Gy total body irradiated B16F10 tumor bearing mice. We characterized the phenotype of the transferred product by flow cytometry and then assessed their tumor control by measuring the tumor area every other day with clippers. For metabolic assays we utilized the 2-NBDG glucose uptake dye and the real time energy flux analysis by seahorse.ResultsSole inhibition of PI3Kδ or PI3Kγ in vitro promoted greater tumor immunity and survival compared to dual inhibition. To understand how PI3Kδ or PI3Kγ blockade improved T cell therapy, we assessed their phenotype. CAL101 treatment produced more CD62LhiCD44lo T cells compared to IPI-459, while TGR-1202 enriched mostly CD62LhiCD44hi T cells. Because decreased T cell differentiation is associated with mitochondrial metabolism, we focused on CAL101 treated T cells to study their metabolism. We found that CAL101 decreased glucose uptake and increased mitochondrial respiration in vitro, indicating augmented mitochondrial function.ConclusionsThese findings indicate that blocking PI3Kδ is sufficient to mediate lasting tumor immunity of adoptively transferred T cells by preventing premature differentiation and improving mitochondrial fitness. Our data suggest that addition of CAL101 to ACT expansion protocols could greatly improve T cell therapies for solid tumors by preventing T cell differentiation and improving mitochondrial function.

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