Regeneration Of Pancreas Research Articles

Serotonin promotes acinar dedifferentiation following pancreatitis-induced regeneration in the adult pancreas.

The exocrine pancreas exhibits a distinctive capacity for tissue regeneration and renewal following injury. This regenerative ability has important implications for a variety of disorders, including pancreatitis and pancreatic cancer, diseases associated with high morbidity and mortality. Thus, understanding its underlying mechanisms may help in developing therapeutic interventions. Serotonin has been recognized as a potent mitogen for a variety of cells and tissues. Here we investigated whether serotonin exerts a mitogenic effect in pancreatic acinar cells in three regenerative models, inflammatory tissue injury following pancreatitis, tissue loss following partial pancreatectomy, and thyroid hormone-stimulated acinar proliferation. Genetic and pharmacological techniques were used to modulate serotonin levels in vivo. Acinar dedifferentiation and cell cycle progression during the regenerative phase were investigated over the course of 2 weeks. By comparing acinar proliferation in the different murine models of regeneration, we found that serotonin did not affect the clonal regeneration of mature acinar cells. Serotonin was, however, required for acinar dedifferentiation following inflammation-mediated tissue injury. Specifically, lack of serotonin resulted in delayed up-regulation of progenitor genes and delayed the formation of acinar-to-ductal metaplasia and defective acinar cell proliferation. We identified serotonin-dependent acinar secretion as a key step in progenitor-based regeneration, as it promoted acinar cell dedifferentiation and the recruitment of type 2 macrophages. Finally, we identified a regulatory Hes1-Ptfa axis in the uninjured adult pancreas, activated by zymogen secretion. Our findings indicated that serotonin plays a critical role in the regeneration of the adult pancreas following pancreatitis by promoting the dedifferentiation of acinar cells.

Distinct temporal regulation of NFATc1 activity safeguards proper regeneration of the exocrine pancreas

Background: In response to acute pancreatitis, surviving acinar cells transiently dedifferentiate and repopulate the exocrine compartment or persist in a metaplastic state that eventually triggers pancreatic atrophy and exocrine insufficiency. Recent evidence suggests that developmental and inflammatory transcription factors effectively control the pancreatic regeneration program.

Distinct temporal regulation of NFATc1 activity safeguards proper regeneration of the exocrine pancreas

Distinct temporal regulation of NFATc1 activity safeguards proper regeneration of the exocrine pancreas

Minireview: Emerging Concepts in Islet Macrophage Biology in Type 2 Diabetes.

Chronic systemic inflammation is a hallmark feature of obesity and type 2 diabetes. Both resident and recruited islet macrophages contribute to the proinflammatory milieu of the diabetic islet. However, macrophages also appear to be critical for β-cell formation during development and support β-cell replication in experimental models of pancreas regeneration. In light of these findings, perhaps macrophages in the islet need to be viewed more as a fulcrum where deleterious inflammatory activation is balanced with beneficial tissue repair processes. Undoubtedly, defining the factors that contribute to the ontogeny, heterogeneity, and functionality of macrophages in normal, diseased, and regenerating islets will be necessary to determine whether that fulcrum can be moved to preserve functional β-cell mass in persons with diabetes. The intent of this review is to introduce the reader to emerging concepts of islet macrophage biology that may challenge the perception that macrophage accumulation in islets is merely a pathological feature of type 2 diabetes.

The potential roles of EZH2 in regenerative medicine.

Enhancer of zeste homolog 2 (EZH2), a catalytic component of polycomb repressive complex 2, serves as a histone methyltransferase toward histone H3K27 trimethylation and also recruits DNA methyltransferases to regulate gene expression and chromatin structure. Accumulating evidence indicates the critical roles of EZH2 in stem cell maintenance and cell fate decision in differentiation into specific cell lineages. In this article, we review the updated progress in the field and the potential application of EZH2 in regenerative medicine including nervous system, muscle, pancreas, and dental pulp regeneration.

Effect of metformin and pioglitazone on β-catenin and biochemical markers in sitagliptin-induced pancreatitis in diabetic rats

This study was designed to investigate effect of metformin or pioglitazone on β-catenin and biochemical indicators in sitagliptin-induced pancreatitis. Type 2 diabetes mellitus was induced by high-fat diet/low-dose streptozotocin. Six groups (n = 8) were used: diabetic control group and five treated groups given, for 6 weeks by oral gavage, metformin (100 mg/kg/day), pioglitazone (20 mg/kg/day), sitagliptin (30 mg/kg/day), metformin + sitagliptin (MS), and pioglitazone + sitagliptin (PS). Body weight (BW) and biochemical parameters (fasting blood sugar (FBS), glycated hemoglobin (HbA1c), insulin, total cholesterol (TC), triglycerides (TG), malondialdehyde (MDA), and amylase) were measured. Pancreatic sections were examined using hematoxylin and eosin staining and immunohistochemical staining for β-catenin protein. Only pioglitazone significantly increased BW. All treatments significantly decreased FBS, HbA1c, TC, TG, MDA, and amylase minimally with sitagliptin and maximally with combination therapies. Moreover, all treatments significantly increased insulin except pioglitazone which showed a nonsignificant decrease. Both metformin and pioglitazone ameliorated the diabetic-induced changes while sitagliptin-treated rats showed signs suggestive of pancreatitis. Sitagliptin failed to inhibit the inappropriately increased β-catenin expression predisposing for pancreatitis but helping regenerate streptozotocin-damaged islets. Metformin and pioglitazone alone or combined with sitagliptin decreased the inappropriate β-catenin expression. In conclusion, the decrease in β-catenin seems to be involved in reversal of sitagliptin-associated pancreatitis by metformin or pioglitazone. The better regeneration of islets with metformin and pioglitazone, than sitagliptin, may be due to better effectiveness in controlling diabetes. Sitagliptin should be used in combination with metformin or pioglitazone. Further studies are needed to determine mechanisms underlying role of Wnt/β-catenin in regeneration of islets and exocrine pancreas.

Another Understanding of the Model of Genetic Code Theoretical Analysis

At present the model of the genetic code (the code of protein biosynthesis) proposed almost 50 years ago by M. Nirenberg and F. Crick has undergone severe erosion. Tactically, it is true that triplicity and the synonymous degeneracy are unmistakable. But the Nirenberg-Crick postulate about unambiguous coding of amino acids, i.e., the strategy raises reasonable doubt. The reasons to doubt showed up very early: it turned out that the triplet UUU codes both phenylalanine and leucine, which was inconsistent with the declaration of the unambiguity of the DNA-RNA encoding of amino acids in proteins. On the other hand, the ambiguity automatically stems from the Wobble Hypothesis by F. Crick relating to the wobbling of the third nucleotide in codons, (random, undetermined behavior), which means the 3’-5’ codon-anticodon pair is not involved in the encoding, and represents a “steric crutch”. In fact, amino acids are coded not by triplet, but by doublet of nucleotides in a triplet, according to “Two-out-of-Three” rule by Ulf Lagerkvist. From this perspective, the codon families split into two classes: 32 codon-synonym triplets and 32 codon triplets with undetermined coding functions, that is inherent to one of the 32 codons UUU. These “undetermined” codons have called homonyms. They are ambiguous as they potentially and simultaneously encode two different amino acids, or amino acid and the stop function. However, the ambiguity is overcome in real protein biosynthesis. This is due to the sign orientations of ribosomes within mRNA contexts. This is the way the semantics of the codon-homonyms occur, as an exact analogy of the consciousness work in the human languages, abounding with homonyms. This turn in the understanding of the protein code, as actual text formation, leads to a strong idea of the genome as a quasi-intelligent biocomputer structure of living cells. Ignoring this leads to erroneous and dangerous works of genetic engineering, the most important results are Synthia bacteria with synthetic genome and GM foods. Protein biosynthesis is a key, but not the only basic information function of chromosomes. There are other, no less important, holographic and quantum non-locality functions related to morphogenesis. In this plane, the work of the genome, as a quantum biocomputer, occurs on the wave level. Here the main function is regulatory quantum broadcasting of genetic-metabolic information on the intercellular, tissue and organism levels using a coherent photon DNA radiation and its nonlinear vibrational states (sound). DNA information presents itself in the form of dynamically polarized holograms as well as phantom DNA structures. In the interpretation of the quantum work of the genome almost everything is hypothetical. Nevertheless, we have created a laser technology, to some extent simulating “sign wave” states of the genome, and are able to transmit genetic and genetic-metabolic information. Manifestations of phantom DNA (fDNK), which we managed to detect in 1984 but published only in 1991 [Gariaev et al., 1991], are particularly interesting. Now we can produce fDNK with our laser techniques and materialize it as a material structure in the PCR system [Gariaev et al., 2014 (a) Gariaev et al., 2014 (b)], as it was done earlier, but in their own way, by the team of Nobel Prize laureate, Professor Luc Montagnier [Montagnier et al., 2012]. However, back in 2007 and 2009 we demonstrated far-distance quantum transmission of genetic information for pancreas regeneration in rats [Gariaev et al., 2007; Gariaev, 2009]. These data are the basis of Linguistic Wave Genetics (LWG). The practical use of LWG principles is potentially large. So far, we have made precedents of regeneration of teeth, pancreas, and retina with full restoration of vision, cured cystic fibrosis and Down Syndrome, and returned mobility to the paralyzed. LWG provides a method to program stem cells. LWG makes it possible to, in an environmentally friendly way selectively destroy pathogenic bacteria and viruses, insect pests and weeds in agriculture. LWG lays the foundations for quantum computing instead of digital.

Regeneration and repair of the exocrine pancreas.

Pancreatitis is caused by inflammatory injury to the exocrine pancreas, from which both humans and animal models appear to recover via regeneration of digestive enzyme-producing acinar cells. This regenerative process involves transient phases of inflammation, metaplasia, and redifferentiation, driven by cell-cell interactions between acinar cells, leukocytes, and resident fibroblasts. The NFκB signaling pathway is a critical determinant of pancreatic inflammation and metaplasia, whereas a number of developmental signals and transcription factors are devoted to promoting acinar redifferentiation after injury. Imbalances between these proinflammatory and prodifferentiation pathways contribute to chronic pancreatitis, characterized by persistent inflammation, fibrosis, and acinar dedifferentiation. Loss of acinar cell differentiation also drives pancreatic cancer initiation, providing a mechanistic link between pancreatitis and cancer risk. Unraveling the molecular bases of exocrine regeneration may identify new therapeutic targets for treatment and prevention of both of these deadly diseases.

The role of pancreatic stellate cells in pancreas regeneration in copper-deficient diet model in rats

The role of pancreatic stellate cells in pancreas regeneration in copper-deficient diet model in rats

Very small embryonic-like stem cells are involved in regeneration of mouse pancreas post-pancreatectomy.

IntroductionDespite numerous research efforts, mechanisms underlying regeneration of pancreas remains controversial. Views are divided whether stem cells are involved during pancreatic regeneration or it involves duplication of pre-existing islets or ductal cells or whether pancreatic islet numbers are fixed by birth or they renew throughout life. Pluripotent embryonic stem (ES) and induced pluripotent stem (iPS) cells have been used by several groups to regenerate diabetic mouse pancreas but the beneficial effects are short-lived. It has been suggested that cells obtained after directed differentiation of ES/iPS cells resemble fetal and not their adult counterparts; thus are functionally different and may be of little use to regenerate adult pancreas. A novel population of pluripotent very small embryonic-like stem cells (VSELs) exists in several adult body tissues in both mice and humans. VSELs have been reported in the mouse pancreas, and nuclear octamer-binding transcription factor 4 (OCT-4) positive, small-sized cells have also been detected in human pancreas. VSELs are mobilized into peripheral blood in streptozotocin treated diabetic mice and also in patients with pancreatic cancer. This study aimed to evaluate whether VSELs are involved during regeneration of adult mouse pancreas after partial pancreatectomy.MethodsMice were subjected to partial pancreatectomy wherein almost 70% of pancreas was surgically removed and residual pancreas was studied on Days 1, 3 and 5 post-surgery.ResultsVSELs were detected in Hematoxylin and Eosin stained smears of pancreatic tissue as spherical, small sized cells with a large nucleus surrounded by a thin rim of cytoplasm and could be sorted as LIN-/CD45-/SCA-1+ cells by flow cytometry. Results reveal that although neutrophils with multi-lobed nuclei are mobilized into the pancreas on day 1 after pancreatectomy, by day 5 VSELs with spherical nuclei, high nucleo-cytoplasmic ratio and nuclear OCT-4 are mobilized into the residual pancreas. VSELs undergo differentiation and give rise to PDX-1 and OCT-4 positive progenitors which possibly regenerate both acinar cells and islets.ConclusionsResults provide direct evidence supporting the presence of VSELs in adult mouse pancreas and their role during regeneration. VSELs are an interesting alternative to ES/iPS cells to regenerate a diabetic pancreas in future.

Frontiers in research on pancreas development and regeneration

Frontiers in research on pancreas development and regeneration

Phytochemical and Pharmacological Properties ofGymnema sylvestre: An Important Medicinal Plant

Gymnema sylvestre (Asclepiadaceae), popularly known as “gurmar” for its distinct property as sugar destroyer, is a reputed herb in the Ayurvedic system of medicine. The phytoconstituents responsible for sweet suppression activity includes triterpene saponins known as gymnemic acids, gymnemasaponins, and a polypeptide, gurmarin. The herb exhibits a broad range of therapeutic effects as an effective natural remedy for diabetes, besides being used for arthritis, diuretic, anemia, osteoporosis, hypercholesterolemia, cardiopathy, asthma, constipation, microbial infections, indigestion, and anti-inflammatory. G. sylvestre has good prospects in the treatment of diabetes as it shows positive effects on blood sugar homeostasis, controls sugar cravings, and promotes regeneration of pancreas. The herbal extract is used in dietary supplements since it reduces body weight, blood cholesterol, and triglyceride levels and holds great prospects in dietary as well as pharmacological applications. This review explores the transition of a traditional therapeutic to a modern contemporary medication with an overview of phytochemistry and pharmacological activities of the herb and its phytoconstituents.

The roles of micro RNA in pancreas development and regeneration

Presence of sufficient number of functional glucose responsive β-cells is indispensable for normal glucose homeostasis. Diabetes mellitus is a chronic disease associated with loss or reduction of β-cell mass and not β-cell mass. MicroRNAs are small non-coding RNAs that are involved in different biological processes including development, cell proliferation, stress response, and tumor pathogenesis. MicroRNAs fine-tune the gene expression level post-transcriptionally either by mRNA degradation or translational repression. In the past few years, several miRNAs have been introduced as new critical players for pancreas development, function, and regeneration. Deregulation of several microRNAs is found in animal models of diabetes, as well as in diabetic patients. Therefore, it is essential to understand the roles of these microRNAs in β-cell generation and physiology, as well as the biological consequences of their functional impairment. Biomedical Reviews 2013; 24: 57-65.

Regeneration from acute pancreatitis requires transcriptional silencing of NFATc1

Introduction: Tissue injury initiates a complex regenerative programme ensuring complete restoration of organ structure and function. Understanding the molecular key events in mediation and regeneration from pancreas injury is critical to develop novel therapeutic strategies. Recent evidence suggests important roles for developmental and inflammatory transcription factors in several steps of the regeneration process. Aims: To analyze whether and how the inflammatory transcription factor NFATc1 is involved in the course of acute pancreatitis. Methods: Caerulein and L-Arginin were used to induce acute pancreatitis in different pancreas specific transgenic mice models with differential expression of NFATc1. Mice were sacrificed at different time points after induction of acute pancreatitis to isolate pancreata for further analysis. Gene expression in mice tissue and acinar cell explants were determined by using RT-PCR, immunoblotting, immunofluorescence and immunohistochemical stainings. Local histone modifications on the NFATc1 promoter were investigated by ChIP analysis. Results: Caerulein mediated acute pancreatitis initiates acinar to ductal metaplasia, which goes along with activation of NFATc1 in metaplastic areas of the pancreas. Regeneration of the pancreas requires inactivation of NFATc1 by H3K27 trimethylation mediated by the Polycomb protein EZH2. While pharmacological or genetic inactivation of NFATc1 in mice accelerates pancreas regeneration, sustained activation of NFATc1 overcomes transcriptional silencing and fully prevents restoration of the organ. Conclusion: Our results provide evidence, that transcriptional silencing of NFATc1 by EZH2 is an inevitable prerequisite for sufficient regeneration from acute pancreatitis.

Obestatin Enhances In Vitro Generation of Pancreatic Islets through Regulation of Developmental Pathways

Availability of large amounts of in vitro generated β-cells may support replacement therapy in diabetes. However, methods to obtain β-cells from stem/progenitor cells are limited by inefficient endocrine differentiation. We have recently shown that the ghrelin gene product obestatin displays beneficial effects on pancreatic β-cell survival and function. Obestatin prevents β-cell apoptosis, preserves β-cell mass and stimulates insulin secretion in vitro and in vivo, in both normal and diabetic conditions. In the present study, we investigated whether obestatin may promote in vitro β-cell generation from mouse pancreatic islet-derived precursor cells. Treatment of cultured islets of Langerhans with obestatin (i) enriched cells expressing the mesenchymal/neuronal marker nestin, which is associated with pancreatic precursors; (ii) increased cell survival and reduced apoptosis during precursor selection; (iii) promoted the generation of islet-like cell clusters (ICCs) with increased insulin gene expression and C-peptide secretion. Furthermore, obestatin modulated the expression of fibroblast growth factor receptors (FGFRs), Notch receptors and neurogenin 3 (Ngn3) during islet-derived precursor cell selection and endocrine differentiation. These results indicate that obestatin improves the generation of functional β-cells/ICCs in vitro, suggesting implications for cell-based replacement therapy in diabetes. Moreover, obestatin may play a role in regulating pathways involved in pancreas development and regeneration.

Control of Cell Identity in Pancreas Development and Regeneration

The endocrine and exocrine cells in the adult pancreas are not static, but can change their differentiation state in response to injury or stress. This concept of cells in flux means that there may be ways to generate certain types of cells (such as insulin-producing β-cells) and prevent formation of others (such as transformed neoplastic cells). We review different aspects of cell identity in the pancreas, discussing how cells achieve their identity during embryonic development and maturation, and how this identity remains plastic, even in the adult pancreas.

Effects of vacuum-assisted closure and Drotrecogin alpha on inflammatory markers in severe acute pancreatitis

In severe acute pancreatitis (SAP) inflammatory processes foster necrosis, cellular lysis and liberation of vasoactive substances associated with multiple organ failure. The effects of vacuum-assisted closure and Drotrecogin alpha on inflammatory cytokines were evaluated in SAP patients with infected necrosis. Methods: Forty-six patients were included in three groups: Group 1, necrosectomy and abdominal cavity washing; Group 2, necrosectomy plus vacuum-assisted closure (VAC), and Group 3, necrossectomy plus VAC plus Drotrecogin alpha. Immunoreactive IL-32, TNF-α, IL-6, TGF-β and IL-2 cytokines were quantified with ELISA method. Results: IL-32 was significantly increased in all patients, predominantly the non-survivor of Group 3 (p 0.0001). Group 2 maintained increased IL-32 levels throughout. Peak TNF-α was observed in non-survivors of Groups 1 and 2, with a frank tendency to decrease in Group 3. The IL-6 was increased, sustained throughout the study, peaking at the onset in non-survivors. At the end IL-6 tended to diminish, predominantly in survivors. TNF-α and IL-6 were significantly increased on hospitalization, with a maximum peak in non-survivors of all groups. Initial values of TGF-β were significantly increased in survivors of the three groups, and were significantly diminished in non-survivors; affecting pancreas regeneration and favoring systemic inflammation, with possible multiple-organ repercussions. IL-2 levels were elevated, predominantly in non-survivors of Group 1. There was positive correlation between the increase IL-32 and TNF-α, and negative correlation between the increase in TNF-α and decrease in TGF-β; and, a tendency for negative correlation between the IL-2 increased and TGF-β levels. Conclusion: We found a generalized, sustained inflammatory state that fosters a torpid outcome in SAP patients.

Bmi1 Is Required for Regeneration of the Exocrine Pancreas in Mice

Bmi1 is a member of the Polycomb protein family and represses transcription by modifying chromatin organization at specific promoters. Bmi1 is implicated in the control of stem cell self-renewal and has been shown to regulate cell proliferation, tissue homeostasis, and differentiation. Bmi1 is present in a subpopulation of self-renewing pancreatic acinar cells and is expressed in response to pancreatic damage. We investigated the role of Bmi1 in regeneration of exocrine pancreas. Acute pancreatitis was induced in Bmi1(-/-) mice with cerulein; pancreatic cell regeneration, differentiation, and apoptosis were assessed. Cultured Bmi1(-/-) and wild-type primary acini were analyzed in vitro to determine acinar-specific consequences of Bmi1 deletion. To investigate cell autonomous versus non-cell autonomous roles for Bmi1 in vivo, pancreatitis was induced in Bmi1(-/-) mice reconstituted with a wild-type hematopoietic system. Bmi1 expression was up-regulated in the exocrine pancreas during regeneration after cerulein-induced pancreatitis. Exocrine regeneration was impaired following administration of cerulein to Bmi1(-/-) mice. Pancreata of Bmi1(-/-) mice were hypoplastic, and the exocrine pancreas was replaced with ductal metaplasia that had increased apoptosis and decreased cell proliferation compared with that of wild-type mice. Expression of Cdkn2a and p53-dependent apoptotic genes was markedly up-regulated in Bmi1(-/-) pancreas compared with wild-type mice after injury. Furthermore, after transplantation of bone marrow from wild-type to Bmi1(-/-) mice, the chimeric mice had intermediate levels of pancreatic hypoplasia and significant but incomplete rescue of impaired exocrine regeneration after cerulein injury. Bmi1 contributes to regeneration of the exocrine pancreas after cerulein-induced injury through cell autonomous mechanisms, in part by regulating Cdkn2a expression, and non-cell autonomous mechanisms.

Protective effect of transplanted bone marrow mononuclearcells (BMMNCs) in organ damage caused due to streptozotocin (STZ) induced diabetes

Diabetes is a rapidly growing health problem; however, there is currently no effective therapy for diabetes. We know that prolonged diabetes leads to damage of various organs apart from pancreas such as kidney and liver and the role of bone marrow mononuclear cells (BMMNCs) is not clearly understood in regeneration of these organs. In this study, we transplanted chloromethylbenzamido-1,1’-dioctadecyl-3,3,3’,3’-tetramethylindocarbocyanine perchlorate (CM-DiI) labeled BMMNCs in streptozotocin (STZ) induced mice and tracked them in various affected organs. We observed, through histological studies that intravenously transplanted CM-DiI labeled BMMNCs were found in acinar regions of the pancreas and not in islet regions, but regenerated islets in diabetic mice. Interestingly, these cells were not found in the kidney and liver of diabetic mice, but these organs regenerated. Also, there was a significant drop in blood glucose levels after the transplantation. We concluded that transplanted BMMNCs incorporated in the acinar region of the pancreas and not in any other organs, but aided in the regeneration of pancreas, liver and kidney. The transplanted BMMNCs also helped in reduction of blood glucose levels. Key words: Bone marrow mononuclear cells, diabetes, transplantation, organ regeneration.

FABRICATION AND PLASMA MODIFICATION OF POLYMER SCAFFOLDS FOR REGENERATIVE AND REPLACEMENT MEDICINE.

Materials that serve as analogues for the native extra-cellular matrix (ECM) can be used in medicine to aid in either the reconstruction or regeneration of damaged tissue and organs. Polymer matrices have been used for regeneration of bone, liver, pancreas, skin and other tissues. Macroporous. biodegradable polymer scaffolds have been prepared by numerous techniques including solvent casting/salt leaching, phase separation, solvent evaporation, and fiber bonding to form a polymer mesh. The main goal of this research was to apply novel physical processing techniques to fabricate and modify highly porous implantable biodegradable scaffolds. More specifically, this involves fabricating scaffolds using electrospinning, piezoelectric printing, gel sublimation techniques and finally modification of matrixes by plasma treatment in order to control chemical structure and morphology of scaffolds.