Regeneration Of Pancreatic Tissue Research Articles

Silk Fibroin Materials: Biomedical Applications and Perspectives.

The golden rule in tissue engineering is the creation of a synthetic device that simulates the native tissue, thus leading to the proper restoration of its anatomical and functional integrity, avoiding the limitations related to approaches based on autografts and allografts. The emergence of synthetic biocompatible materials has led to the production of innovative scaffolds that, if combined with cells and/or bioactive molecules, can improve tissue regeneration. In the last decade, silk fibroin (SF) has gained attention as a promising biomaterial in regenerative medicine due to its enhanced bio/cytocompatibility, chemical stability, and mechanical properties. Moreover, the possibility to produce advanced medical tools such as films, fibers, hydrogels, 3D porous scaffolds, non-woven scaffolds, particles or composite materials from a raw aqueous solution emphasizes the versatility of SF. Such devices are capable of meeting the most diverse tissue needs; hence, they represent an innovative clinical solution for the treatment of bone/cartilage, the cardiovascular system, neural, skin, and pancreatic tissue regeneration, as well as for many other biomedical applications. The present narrative review encompasses topics such as (i) the most interesting features of SF-based biomaterials, bare SF's biological nature and structural features, and comprehending the related chemo-physical properties and techniques used to produce the desired formulations of SF; (ii) the different applications of SF-based biomaterials and their related composite structures, discussing their biocompatibility and effectiveness in the medical field. Particularly, applications in regenerative medicine are also analyzed herein to highlight the different therapeutic strategies applied to various body sectors.

Sungkai Leaves (Peronema Canescens) Ameliorates the Plasma Glucose Profile and the Pancreatic Histopathological Regeneration of Diabetic Wistar Rats

This study aims to test how effective oral infusion of sungkai leaves is on the profile of changes in blood plasma glucose levels and regeneration of pancreatic tissue in diabetic Wistar rats. This research method is a proper experimental design with a randomized pre-post-test design with a control group. The study's results illustrate differences in mice's blood sugar levels before and after the intervention, showing a decrease in blood sugar levels in the K(+), P-1, and P-2 groups, while in the K(+), P-1, and P groups -2. The K(-) group shows a decreasing trend. Apart from that, histopathological examination of the pancreas also showed improvement in each treatment group with a decreasing percentage of pathological events. In conclusion, blood plasma glucose examination showed a significant difference, positively affecting diabetes mellitus, while the rate of pancreatic tissue injury showed a similar form. Keywords: Sungkai leaves, plasma glucose, pancreatic regeneration

Recombinant Reg3α Prevents Islet β-Cell Apoptosis and Promotes β-Cell Regeneration.

Progressive loss and dysfunction of islet β-cells has not yet been solved in the treatment of diabetes. Regenerating protein (Reg) has been identified as a trophic factor which is demonstrated to be associated with pancreatic tissue regeneration. We previously produced recombinant Reg3α protein (rReg3α) and proved that it protects against acute pancreatitis in mice. Whether rReg3α protects islet β-cells in diabetes has been elusive. In the present study, rReg3α stimulated MIN6 cell proliferation and resisted STZ-caused cell death. The protective effect of rReg3α was also found in mouse primary islets. In BALB/c mice, rReg3α administration largely alleviated STZ-induced diabetes by the preservation of β-cell mass. The protective mechanism could be attributed to Akt/Bcl-2/-xL activation and GRP78 upregulation. Scattered insulin-expressing cells and clusters with small size, low insulin density, and exocrine distribution were observed and considered to be neogenic. In isolated acinar cells with wheat germ agglutinin (WGA) labeling, rReg3α treatment generated insulin-producing cells through Stat3/Ngn3 signaling, but these cells were not fully functional in response to glucose stimulation. Our results demonstrated that rReg3α resists STZ-induced β-cell death and promotes β-cell regeneration. rReg3α could serve as a potential drug for β-cell maintenance in anti-diabetic treatment.

Evidence of Stem Cells Mobilization in the Blood of Patients with Pancreatitis: A Potential Link with Disease Severity.

A growing number of studies indicate the potential involvement of various populations of bone marrow-derived stem cells (BMSCs) in tissue repair. However, the mobilization of BMSCs to the peripheral blood (PB) in acute and chronic pancreatitis (AP and CP) has not been investigated. A total of 78 patients were assigned into AP, CP, and healthy control groups in this study. Using flow cytometry, we found that VSELs, EPCs, and CD133+SCs were mobilized to the PB of patients with both AP and CP. Interestingly, AP and CP patients exhibited lower absolute number of circulating MSCs in the PB compared to healthy individuals. SC mobilization to the PB was more evident in patients with AP than CP and in patients with moderate/severe AP than mild AP. Using ELISA, we found a significantly increased HGF concentration in the PB of patients with AP and SDF1α in the PB of patients with CP. We noted a significant positive correlation between SDF1α concentration and the mobilized population of CD133+SCs in AP and between C5a and the mobilized population of VSELs moderate/severe AP. Thus, bone marrow-derived SCs may play a role in the regeneration of pancreatic tissue in both AP and CP, and mobilization of VSELs to the PB depends on the severity of AP.

Adipose-Derived Stem Cells Preincubated with Green Tea EGCG Enhance Pancreatic Tissue Regeneration in Rats with Type 1 Diabetes through ROS/Sirt1 Signaling Regulation.

Type 1 diabetes stem-cell-based therapy is one of the best therapeutic approaches for pancreatic damage treatment due to stem cell tissue regeneration. Epigallocatechin gallate (EGCG) is one of the active components found in green tea. Experimental results suggest that EGCG shows beneficial effects on cell protection. This study explores whether a better pancreatic regeneration therapeutic effect could be found in mesenchymal stem cells pretreated with EGCG compared to stem cells without EGCG pretreatment. A cell model confirmed that adipose-derived stem cells (ADSC) incubated with EGCG increase cell viability under high-glucose (HG) stress. This is due to survival marker p-Akt expression. In an animal model, type 1 diabetes induced the activation of several pathological signals, including islet size reduction, extracellular fibrotic collagen deposition, oxidative stress elevation, survival pathway suppression, apoptosis signaling induction, and Sirt1 antioxidant pathway downregulation. Ordinary ADSC transplantation slightly improved the above pathological signals. Further, EGCG-pretreated ADSC transplantation significantly improved the above pathological conditions. Taken together, EGCG-pretreated ADSCs show clinical potential in the treatment of patients with type 1 diabetes through the regeneration of damaged pancreatic tissues.

Immunopathology of Type 1 Diabetes and Immunomodulatory Effects of Stem Cells: A Narrative Review of the Literature.

Type 1 Diabetes (T1D) is a complex autoimmune disorder which occurs as a result of an intricate series of pathologic interactions between pancreatic β-cells and a wide range of components of both the innate and the adaptive immune systems. Stem-cell therapy, a recently-emerged potentially therapeutic option for curative treatment of diabetes, is demonstrated to cause significant alternations to both different immune cells such as macrophages, natural killer (NK) cells, dendritic cells, T cells, and B cells and non-cellular elements, including serum cytokines and different components of the complement system. Although there exists overwhelming evidence indicating that the documented therapeutic effects of stem cells on patients with T1D are primarily due to their potential for immune regulation rather than pancreatic tissue regeneration, to date, the precise underlying mechanisms remain obscure. On the other hand, immune-mediated rejection of stem cells remains one of the main obstacles to regenerative medicine. Moreover, the consequences of efferocytosis of stem-cells by the recipients' lung-resident macrophages have recently emerged as a mechanism responsible for some immune-mediated therapeutic effects of stem-cells. This review focuses on the nature of the interactions amongst different compartments of the immune systems which are involved in the pathogenesis of T1D and provides an explanation as to how stem cell- based interventions can influence immune system and maintain the physiologic equilibrium.

Icariin Promote Stem Cells Regeneration and Repair Acinar Cells in L-arginine / Radiation -Inducing Chronic Pancreatitis in Rats.

Objective:Chronic Pancreatitis (CP) is a multifactorial disease. It was characterized by severe inflammation and acinar cell destruction. Thus, the present study was initiated to evaluating the ability of bone marrow-based mesenchymal stem cell (MSCs) combined with Icariin to restore and regenerate acinar cells in the pancreas of rats suffering chronic pancreatitis.Methods:Chronic pancreatitis was induced in rats via both L-arginine plus radiation, repeated L-arginine injection (2.5g/Kg body-weight, 1, 4,7,10,13,16,19 days), then, on day 21, rats were exposed to a single dose of gamma-radiation (6 Gy), which exacerbate injury of pancreatic acinar cells. One day after irradiation, rats were treated with either MSCs (1 × 107 /rat, once, tail vein injection) labeled PKH26 fluorescent linker dye and/or Icariin (100 mg/Kg, daily, orally) for 8 weeks.Results:Icariin promotes MSCs proliferation boosting its productivity in vitro. MSCs, and/or icariin treatments has regulated molecular factors TGF-β/PDGF and promoted the regeneration of pancreatic tissues by releasing PDX-1 and MafA involved in the recruitment of stem/progenitor cell in the tissue, and confirmed by histopathological examination. Moreover, a significant decrease in IL-8 and TNF-α cytokines with significant amelioration of myeloperoxidase activity were noted. As well as, reduction in MCP-1 and collagen type-1 levels along with Hedgehog signaling down-regulating expression in such cells, Patched-1, Smoothened, and GLi-1.Conclusion:The potent bioactive therapeutic Icariin combined with MSCs induces a significantly greater improvement, compared to each therapy alone.

The effect of exosomes derived from mesenchymal stem cells in the treatment of induced type 1 diabetes mellitus in rats.

The aim of the current study was to evaluate the therapeutic and regenerative effects of MSCs derived exosomes in the treatment of type 1 DM and to compare its effects with MSCs themselves. The experiment was done on forty albino rats grouped as follows, group (1): Ten healthy rats, group (2): Ten induced type 1 DM rats, group (3): Ten induced type 1 DM rats received exosomes intraperitoneally, and group (4): Ten induced type 1 DM rats received MSCs intraperitoneally. Serum glucose and plasma insulin levels were assessed weekly. QRT-PCR was done to assess regeneration of pancreatic beta cells by measuring insulin, Pdx1, Smad2, Smad3 and TGFβ genes. Additionally, histopathological and immune-histochemical examinations were done to confirm pancreatic tissue regeneration. Regarding the assessed genes (insulin, Pdx1, Smad2, Smad3 and Tgfβ) gene expression in MSCs treated group showed significant increase compared to diabetic group (p value < 0.001) and gene expression in exosomes treated group was increased significantly compared to diabetic and MSCs treated groups (p value < 0.001). Histopathological and immune-histochemical examination revealed regeneration of pancreatic islets in both treated groups. MSCs Derived exosomes showed superior therapeutic and regenerative results than MSCs themselves.

EXPERIMENTAL STUDIES OF THE EFFECT OF ELECTROSURGICAL AND STANDARD TECHNIQUES ON PANCREATIC RESTORATION

The aim: There have been investigated the specific features of pancreatic resection with the use of electrosurgical methods on experimental models of clinical operations. Pancreatic tissue regeneration at the surgical site have been studied when employing monopolar, bipolar, electric welding methods as compared with standard surgical technique. Materials and methods: The study was performed on 40 white laboratory rats. Pancreatic resection was conducted by standard surgical technique or by welding with electrocoagulation device "Patonmed EWD-300", high-energy electrosurgical device in bipolar mode and in monopolar mode. The pancreatic tissue was examined immediately after the surgery and at 3, 7 and 21 days postoperatively. Results: In early terms following standard surgery there was seen more severe inflammation and the volume of newly formed connective tissue got increased faster than after the electrosurgical technique. Pancreatic ducts developed in newly formed tissue after the use of each type of electroresection, whereas that event was not observed following standard surgery. When using electrosurgery in monopolar mode, the area of coagulative necrosis was found to be less dense than after resection performed in bipolar mode. Conclusions: Based on the findings, we can conclude that each of the above types of electroresection reduces surgery time, lowers bleeding risks, contributes to formation of the more adequate sealing on the resection surface with no complications of the recovery process.

Recombinant Reg3α Protein Protects Against Streptozotocin-Induced β-cell Damage and Diabetes

Regenerating (Reg) proteins have been identified as putative trophic factors, which are involved in pancreatic tissue regeneration and neogenesis. Our recent research found that recombinant Reg3α protein (rReg3α) protects against experimental, acute pancreatitis by alleviating pancreatic acinar cell necrosis and apoptosis. In order to further investigate the potential role of rReg3α in promoting islet β-cell survival against streptozotocin(STZ)-triggered cell death, rReg3α was directly administrated in MIN6 insulinoma cells and STZ-induced type 1 diabetes. Our results demonstrate that rReg3α stimulated MIN6 cell proliferation through Erk1/2 phosphorylation and cyclinD1/CDK4 upregulation mediated by Akt/ATF-2 signaling. Furthermore, it ameliorated STZ-induced cell death via enhanced Bcl-2 and Bcl-xL expression caused by Akt activation and reduced Caspase-3 cleavage. The administration of exogenous rReg3α partially prevented STZ-induced hyperglycemia and weight loss, and totally prevented animal death. The superiority of rReg3α in preserving insulin content and islet β- cell mass, and putatively promoting the regeneration of insulin positive cell clusters suggested its therapeutic potential against diabetes mellitus.

Functional characterization of EZH2 in pancreatic carcinogenesis

ID: 1413. Dual specificity kinase TTK in pancreatic neuroendocrine cancer Marina Hutzler , Harald Schmidt , Brajesh Kaistha , Rita Lawlor , Aldo Scarpa , Thomas Gress , Malte Buchholz 1 Gastroenterology and Endocrinology, Philipps University Marburg, Marburg, Germany Dipartimento ad Attivit a Integrata (DAI) di Patologia e Diagnostica, University of Verona, Verona, Italy Introduction: Pancreatic neuroendocrine tumours are a rare but still very challenging disease, as despite ongoing research, surgical resection still is the only reliable cure. Therefore, about 80 % of patients have a terminal illness and their tumours are still difficult to manage with the currently available chemoand biotherapies obtaining tumour growth stabilization rather than inducing regression. Gene expression analyses of primary tissues from PNET patients identified a number of potential target genes for the development of new therapeutic strategies. Amongst others, we found strong upregulation of the dual specificity kinase TTK, which has been shown before to play an important role during mitosis by inhibiting transition to anaphase until all chromosomes have been attached to the spindle apparatus correctly. Aims: The aim of this study is to elucidate the role of TTK and its value for PNET therapy. Materials & methods: Quantitative realtime PCR, RNAi, cell proliferation and viability assays, Westernblots Results: TTK is strongly overexpressed in pancreatic neuroendocrine tumour tissue. Functional in vitro analyses by siRNA-mediated knockdown of TTK in human as well as in rat PNET cell lines resulted in decreased proliferation and viability of cells, leading to increased apoptosis rates which could be further confirmed by Westernblot analyses of key molecules of the classical apoptosis pathway (Caspase-3 and PARP cleavage). Conclusion: Overexpression of TTK dual specificity kinase in pancreatic neuroendocrine tumours is important for proliferative phenotype of tumour cells and inhibition of TTK leads to apoptotic cell death. Therefore TTK could be a promising target for the treatment of neuroendocrine tumours. Abstract ID: 1416, Oral-3.ID: 1416, Oral-3. Context-dependent epigenetic regulation of NFATc1 transcription in pancreatic plasticity Elisabeth Hessmann , Nai-ming Chen , Clara Lubeseder-Martellato , Jochen Gaedcke , Jens Siveke , Albrecht Neesse , Volker Ellenrieder 1 Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen, Germany 2 II. Med. Klinikum rechts der Isar, TU Munich, Germany Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Germany West German Cancer Center Essen, Germany Introduction: Cellular plasticity of the pancreas highly contributes to its enormous regenerative potential upon acinar insults, but also causes therapeutic resistance in pancreatic cancer (PDAC) treatment. On the molecular level, regulation of cellular plasticity involves epigenetic mechanisms that transcriptionally control key-signatures of tissue adaptation. Transcriptional activation of the oncogenic Nuclear Factor of Activated T-cell (NFAT) c1 transcription factor significantly contributes to PDAC cell plasticity. Nevertheless, how epigenetic alterations converge on transcriptional regulation of NFATc1 remains elusive. Aims: To investigate how epigenetic regulation impacts on NFATc1 transcription in pancreatic plasticity. Materials&methods: NFATc1 function and regulationwere studied in the regenerative pancreas upon caerulein-induced acinar cell damage and in various in vitroand in vivo PDAC-models. EZH2-dependency of NFATc1 expression was determined upon genetic or pharmacological EZH2Abstracts / Pancreato S10 inhibition. NFATc1 promoter activity was investigated by ChIP-Assays in pancreatic tissue and cells. Co-expression of EZH2 and NFATc1 was validated in micro-dissected PDAC cells from human samples. Results: Pancreatic tissue regeneration requires silencing of the NFATc1 promoter by the Polycomb-Repressor-Complex member EZH2 to circumvent organ atrophy and exocrine insufficiency. In contrast, EZH2 activation in PDAC shows inverse effects on NFATc1 promoter regulation and promotes PDAC cell plasticity by enhancing NFATc1 transcription. Oncogenic mutation of Kraswas identified as the crucial genetic hit responsible for the functional switch in EZH2-dependent regulation of NFATc1 transcription. Conclusion: These data complement previous descriptions of Polycomb-independent EZH2 functions and emphasize how epigenetic mechanisms integrate into genomic alterations in PDAC. Consequently, pharmacological inhibition of EZH2 represents a beneficial strategy to overcome oncogenic NFATc1 activity in PDAC.

Inactivation of TGFβ receptor II signalling in pancreatic epithelial cells promotes acinar cell proliferation, acinar-to-ductal metaplasia and fibrosis during pancreatitis.

Determining signalling pathways that regulate pancreatic regeneration following pancreatitis is critical for implementing therapeutic interventions. In this study we elucidated the molecular mechanisms underlying the effects of transforming growth factor-β (TGFβ) in pancreatic epithelial cells during tissue regeneration. To this end, we conditionally inactivated TGFβ receptor II (TGFβ-RII) using a Cre-LoxP system under the control of pancreas transcription factor 1a (PTF1a) promoter, specific for the pancreatic epithelium, and evaluated the molecular and cellular changes in a mouse model of cerulein-induced pancreatitis. We show that TGFβ-RII signalling does not mediate the initial acinar cell damage observed at the onset of pancreatitis. However, TGFβ-RII signalling not only restricts acinar cell replication during the regenerative phase of the disease but also limits ADM formation in vivo and in vitro in a cell-autonomous manner. Analyses of molecular mechanisms underlying the observed phenotype revealed that TGFβ-RII signalling stimulates the expression of cyclin-dependent kinase inhibitors and intersects with the EGFR signalling axis. Finally, TGFβ-RII ablation in epithelial cells resulted in increased infiltration of inflammatory cells in the early phases of pancreatitis and increased activation of pancreatic stellate cells in the later stages of pancreatitis, thus highlighting a TGFβ-based crosstalk between epithelial and stromal cells regulating the development of pancreatic inflammation and fibrosis. Collectively, our data not only contribute to clarifying the cellular processes governing pancreatic tissue regeneration, but also emphasize the conserved role of TGFβ as a tumour suppressor, both in the regenerative process following pancreatitis and in the initial phases of pancreatic cancer.

Role of YAP and TAZ in pancreatic ductal adenocarcinoma and in stellate cells associated with cancer and chronic pancreatitis.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a fibrotic and inflammatory microenvironment that is formed primarily by activated, myofibroblast-like, stellate cells. Although the stellate cells are thought to contribute to tumorigenesis, metastasis and drug resistance of PDAC, the signaling events involved in activation of the stellate cells are not well defined. Functioning as transcription co-factors, Yes-associated protein (YAP) and its homolog transcriptional co-activator with PDZ-binding motif (TAZ) modulate the expression of genes involved in various aspects of cellular functions, such as proliferation and mobility. Using human tissues we show that YAP and TAZ expression is restricted to the centroacinar and ductal cells of normal pancreas, but is elevated in cancer cells. In particular, YAP and TAZ are expressed at high levels in the activated stellate cells of both chronic pancreatitis and PDAC patients as well as in the islets of Langerhans in chronic pancreatitis tissues. Of note, YAP is up regulated in both acinar and ductal cells following induction of acute and chronic pancreatitis in mice. These findings indicate that YAP and TAZ may play a critical role in modulating pancreatic tissue regeneration, neoplastic transformation, and stellate cell functions in both PDAC and pancreatitis.

Stepwise Differentiation of Human Adipose-Derived Mesenchymal Stem Cells Toward Definitive Endoderm and Pancreatic Progenitor Cells by Mimicking Pancreatic Development In Vivo

Pancreatic progenitor (PP) cells are tissue-committed cells, which can differentiate into all kinds of pancreatic cells. They are potential candidates for regeneration of pancreatic tissue. However, it is unfeasible to acquire PP cells from pancreatic tissues and expand them in vitro. Generation of PP cells from adipose tissue-derived mesenchymal stem cells (AD-MSCs) would provide an unlimited source of PP cells. Here we developed a 2-step stepwise protocol, which induced AD-MSCs to generate FOXA2- or SOX17-positive definitive endoderm (DE) (5 days) and pancreatic and duodenal homeobox gene 1 (PDX1)-positive PP cells (4-6 days). By mimicking the developmental progress in embryonic development, we optimized the timing and combination of cytokines to activate the key signaling pathways during pancreatic development. We found that activating the Nodal/Activin signal with Activin A could induce differentiation of AD-MSCs toward DE, which could be further promoted by the Wnt signaling pathway activator Wnt3a. Besides, transient T (BRACHYURY)(+) mesendodermal cells were observed during formation of DE from AD-MSCs. Subsequently, the Wnt signaling pathway inhibitor Dkk1 along with retinoic acid/FGF2 (60 ng/mL) further induced AD-MSC-derived DE cells to differentiate into PDX1-positive PP cells. The derived PP cells were capable to form pancreatic endocrine or exocrine cells. In conclusion, we established a stepwise protocol that could derive DE and PP cells from AD-MSCs. It might provide an unlimited source of autologous PP cells for pancreatic diseases.

A novel animal model for studying pancreatic regeneration by employing photochemical reaction

PurposeWe present photochemical-induced pancreatic necrosis (PIPN) as a novel induction method for studying pancreatic regeneration in an animal model. MethodsPhotosensitive Rose Bengal was injected through the femoral vein in rats, followed by illumination of the surface of the pancreas with a cool halogen light for a period of 20 min. At 3, 6, and 24 h, and 7, 10, 14, and 20 days, experimental animals were sacrificed; all the animals received intravenous injection with 5-bromo-2-deoxyuridine (BrdU) 1 h prior to sacrifice. ResultsAt 3–6 h of induction of PIPN, pancreatic necrosis was superficially observed in the illuminated field. At 24 h, there was a slight increase in the depth and width of the lesion along with appearance of vascular congestion and thrombosis in the lesion. On days 7–10, the area of illumination was totally replaced by necrotic pancreatic tissue, inflammatory cell infiltrates, and newly appearing cellular components, including mesenchymal and epithelial cells, which formed tubular complexes. On day 14, clusters of tubular complexes intermingled with acinar cells, which were proven as newly formed acinar tissue by BrdU staining. On day 20, all the lesions had returned to a normal state of pancreatic tissue. ConclusionThis study demonstrates the potential of PIPN as a valuable method for production of an animal model for studying healing processes or regeneration of pancreatic tissue after injury.

Rosiglitazone promotes pancreatic regeneration in experimental model of acute pancreatitis

Acute pancreatitis is an inflammatory disease of the pancreas caused by release of activated digestive enzymes in the pancreas. A number of therapeutic options have been explored for acute pancreatitis, but none has been unambiguously proven to be effective. Rosiglitazone has been shown to be efficacious in acute pancreatitis; thus, the present study was planned to evaluate the effect of rosiglitazone on pancreatic regeneration. Pancreatitis was induced by l-arginine in rats which were divided into three groups: cholecystokinin (CCK-8), rosiglitazone and vehicle. Rats were sacrificed at four time points after induction of pancreatitis i.e. 24h, day 3, day 14 and day 28 for determination of biochemical parameters and histological examination. Rate of DNA synthesis, immunohistochemistry and RT-PCR were performed at day 3 and day 7. Drug administration was started 2h after last L-arginine injection and continued till the day of sacrifice. The lower levels of enzyme in rosiglitazone-treated group compared to vehicle group proved the efficacy of rosiglitazone treatment in reducing severity of acute pancreatitis. The nucleic acid content and rate of DNA synthesis were significantly higher in rosiglitazone group indicating promotion of pancreatic regeneration. The histopathological score were lower in rosiglitazone group. Rosiglitazone treatment promoted pancreatic regeneration after acute injury. Currently, only symptomatic treatment is available, regeneration of pancreatic tissue can be a future strategy in the management of acute pancreatitis. Further studies are required to support the findings of the present study.

Clusterin Expression in the Early Process of Pancreas Regeneration in the Pancreatectomized Rat

We have previously reported upregulation of clusterin at the time of islet cell regeneration after beta-cell injury. This led us to speculate that clusterin might be involved in the neogenic regeneration of the pancreas. Clusterin expression was examined throughout the process of pancreatic neogenesis in pancreatectomized rats. For in vitro analysis, duct cells were isolated from the rat pancreas and clusterin cDNA was transfected for its overexpression. Clusterin and its mRNA increased significantly in the early phase of regeneration, particularly at 1-3 days after pancreatectomy. Clusterin was transiently expressed in the differentiating acinar cells but faded afterwards. Interestingly, these clusterin cells were negative for PCNA (proliferating cell nuclear antigen), whereas most epithelial cells in ductules in the regenerating tissue showed extensive proliferative activity. Clusterin expression was also detected in some endocrine cells of the regenerating tissue. Transfection of clusterin cDNA into primary cultured duct cells resulted in a 2.5-fold increase in cell proliferation and induced transformation of non-differentiated duct cells into differentiated cells displaying cytokeratin immunoreactivity. Taken together, these results suggest that clusterin may play essential roles in the neogenic regeneration of pancreatic tissue by stimulating proliferation and differentiation of duct cells.

Bone marrow-derived stem cells initiate pancreatic regeneration.

We show that transplantation of adult bone marrow-derived cells expressing c-kit reduces hyperglycemia in mice with streptozotocin-induced pancreatic damage. Although quantitative analysis of the pancreas revealed a low frequency of donor insulin-positive cells, these cells were not present at the onset of blood glucose reduction. Instead, the majority of transplanted cells were localized to ductal and islet structures, and their presence was accompanied by a proliferation of recipient pancreatic cells that resulted in insulin production. The capacity of transplanted bone marrow-derived stem cells to initiate endogenous pancreatic tissue regeneration represents a previously unrecognized means by which these cells can contribute to the restoration of organ function.

Involvement of endogenous cholecystokinin in pancreatic regeneration after cerulein-induced acute pancreatitis.

This study was undertaken to determine the involvement of endogenous cholecystokinin (CCK) in the regeneration of pancreatic tissue after cerulein-induced acute pancreatitis treated by the CCK receptor antagonist L364,718. Acute pancreatitis was induced in rats by s.c. injections of cerulein in gelatin (12 micrograms/kg) three times a day for 2 days with controls receiving saline in gelatin. Rats were then divided into four treatment groups: saline-dimethyl sulfoxide (DMSO) (SD), saline-L364,718 (SA), cerulein-pancreatitis-DMSO (CD), and cerulein-pancreatitis-L364,718 (CA). In the first experiment, rats were treated for 3 or 10 days with DMSO or L364,718 (0.1 mg/kg, twice a day). In the second experiment, rats were treated for 13 days with DMSO or L364,718 (1.0 mg/kg, twice a day). After the rats were killed, pancreata were weighed and evaluated for their total protein, amylase, chymotrypsin, RNA, and DNA. We found that destruction of the pancreatic tissue occurred after cerulein-induced pancreatitis and that regeneration of the tissue was in progress but incomplete after 10 days; the low dose of L364,718 did not prevent regeneration. After 13 days, regeneration was still incomplete but the 1-mg dose of L364,718 strongly inhibited spontaneous regeneration. These data suggest that endogenous CCK is an important and potent trophic factor in the regeneration process of pancreatic tissue following an episode of acute pancreatitis.