Regeneration Of Pancreas Research Articles

Abstract C059: Regulatory Elements of Pancreas Development License the Initiation of Pancreatic Ductal Adenocarcinoma

Abstract Mutations in DNA are a known cause of cancer. However, they become oncogenic only under specific cellular conditions and within certain tissue contexts. Tissue injury often leads to the aberrant activation of developmental pathways, eroding markers of cellular differentiation and giving rise to transient cellular states. These states resemble developmental progenitors, characterized by higher transcriptional plasticity. Oncogenes, particularly KRAS, co-opt cellular plasticity by acting on tissue-specific enhancers, preventing the resolution of acinar plasticity and maintaining the pancreas in a pro-inflammatory phase that progresses to cancer1,2. However, the specific role of tissue-specific enhancers in pancreas regeneration and cancer initiation remains unexplored, and strategies to target these regenerative processes are yet to be developed. Our laboratory investigates non-mutational mechanisms of cancer, with a special interest in the intersection of developmental biology and cancer, aiming to elucidate the processes of cellular plasticity and cancer initiation. Recent studies have shown that acinar cells possess remarkable cellular plasticity, giving rise to a diverse population of cellular states in pancreas regeneration and cancer contexts3-5. We have discovered that the transcription factor Sox4 is necessary for the specification of tuft cells and gastric metaplasia found in chronic pancreatitis and in pancreatic intraepithelial lesions (PanINs). Moreover, we have shown that cellular plasticity has a non-cell autonomous protective effect; losing Sox4 and cellular heterogeneity in PanINs results in a fibrotic and immunosuppressive tumor microenvironment and disease progression. Our results demonstrated that targeting cellular plasticity accelerates or prevents cancer initiation through autonomous and non-autonomous cellular processes6. In this study, we leverage a comprehensive resource of ncRNAs transcribed from enhancer elements of pancreas development, together with their inferred target genes and correlations with clinical outcomes. We focused on an ncRNA associated with the risk of pancreatic cancer. To study its function, we developed two novel mouse strains for tissue-specific deletion, enabling precise manipulation and study of its role in the pancreas and other tissues. Our phenotypic analysis demonstrates that the ncRNA is activated following tissue injury and is essential for developing PanINs. Moreover, we show that it regulates cell-cell communication after tissue injury. This mechanism operates independently of cellular plasticity but significantly creates a pro-inflammatory environment that favors cancer development. Our results demonstrate that enhancer elements are actionable targets to regulate cell fate decisions in regeneration and cancer. Additionally, KRAS-induced cancer initiation depends on developmental regulatory elements, opening the window to develop prophylactic interventions to delay tumor onset. Citation Format: Luis Arnes. Regulatory Elements of Pancreas Development License the Initiation of Pancreatic Ductal Adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C059.

A Single-Cell Atlas of the Murine Pancreatic Ductal Tree Identifies Novel Cell Populations With Potential Implications in Pancreas Regeneration and Exocrine Pathogenesis

Pancreatic ducts form an intricate network of tubules that secrete bicarbonate and drive acinar secretions into the duodenum. This network is formed by centroacinar cells; terminal, intercalated, intracalated ducts; and the main pancreatic duct. Ductal heterogeneity at the single-cell level has been poorly characterized; therefore, our understanding of the role of ductal cells in pancreas regeneration and exocrine pathogenesis has been hampered by the limited knowledge and unexplained diversity within the ductal network. We used small conditional RNA sequencing to comprehensively characterize mouse ductal heterogeneity at single-cell resolution of the entire ductal epithelium from centroacinar cells to the main duct. Moreover, we used organoid cultures, injury models, and pancreatic tumor samples to interrogate the role of novel ductal populations in pancreas regeneration and exocrine pathogenesis. We have identified the coexistence of 15 ductal populations within the healthy pancreas and characterized their organoid formation capacity and endocrine differentiation potential. Cluster isolation and subsequent culturing let us identify ductal cell populations with high organoid formation capacity and endocrine and exocrine differentiation potential invitro, including a Wnt-responsive population, a ciliated population, and FLRT3+ cells. Moreover, we have characterized the location of these novel ductal populations in healthy pancreas, chronic pancreatitis, and tumor samples. The expression of WNT-responsive, interferon-responsive, and epithelial-to-mesenchymal transition population markers increases in chronic pancreatitis and tumor samples. In light of our discovery of previously unidentified ductal populations, we unmask potential roles of specific ductal populations in pancreas regeneration and exocrine pathogenesis. Thus, novel lineage-tracing models are needed to investigate ductal-specific populations invivo.

Age-Related Decline in Pancreas Regeneration Is Associated With an Increased Proinflammatory Response to Injury

Background and AimsThe regenerative capacity of the pancreas diminishes with age. Understanding acinar cell responses to injury and the resolution of regenerative processes is crucial for tissue homeostasis. However, knowledge about the impact of aging on these processes remains limited. MethodsTo investigate the influence of aging on pancreas regeneration, we established a cohort of young (7-14 weeks) and old (18 months) C57bl/6 mice. Experimental pancreatitis was induced using caerulein, and pancreas samples were collected at various timepoints after induction, covering acute damage response, inflammation, peak proliferation, and inflammation resolution. Our analysis involved immunohistochemistry, quantitative imaging, and gene expression analyses.Our study revealed a significant decline in the regenerative capacity of the pancreas in old mice. Despite similar morphology and transcriptional profiles between the pancreas of young and old mice under homeostasis, the aged pancreas is primed to generate an exacerbated proinflammatory reaction in response to injury. Specifically, we observed notable upregulation of Junb expression in acinar cells and aberrant myofibroblast activation in aged pancreas. ConclusionsThe response of acinar cells to injury in the pancreas of aged mice is characterized by an increased susceptibility to inflammation and stromal reactions. Our findings uncover a pre-existing proinflammatory state in aged acinar cells, offering insights into potential strategies to prevent the onset of pancreatic insufficiency and the development of inflammatory conditions. These insights hold implications for preventing conditions such as chronic pancreatitis and pancreatic ductal adenocarcinoma.

BET Inhibition Rescues Acinar-Ductal-Metaplasia and Ciliogenesis and Ameliorates Chronic Pancreatitis-Driven Changes in Mice With Loss of the Polarity Protein Par3

The apical-basal polarity of pancreatic acinar cells is essential for maintaining tissue architecture. However, the mechanisms by which polarity proteins regulate acinar pancreas injury and regeneration are poorly understood. Cerulein-induced pancreatitis was induced in mice with conditional deletion of the polarity protein Par3 in the pancreas. The impact of Par3 loss on pancreas injury and regeneration was assessed by histologic analyses and transcriptional profiling by RNA sequencing. Mice were pretreated with the bromodomain and extraterminal domain (BET) inhibitor JQ1 before cotreatment with cerulein to determine the effect of BET inhibition on pancreas injury and regeneration. Initially, we show that Par3 is increased in acinar-ductal metaplasia (ADM) lesions present in human and mouse chronic pancreatitis specimens. Although Par3 loss disrupts tight junctions, Par3 is dispensable for pancreatogenesis. However, with aging, Par3 loss results in low-grade inflammation, acinar degeneration, and pancreatic lipomatosis. Par3 loss exacerbates acute pancreatitis-induced injury and chronic pancreatitis-induced acinar cell loss, promotes pancreatic lipomatosis, and prevents regeneration. Par3 loss also results in suppression of chronic pancreatitis-induced ADM and primary ciliogenesis. Notably, targeting BET proteins attenuates chronic pancreatitis-induced loss of primary cilia and promotes ADM in mice lacking pancreatic Par3. Targeting BET proteins also attenuates cerulein-induced acinar cell loss and enhances recovery of acinar cell mass and body weight of mice lacking pancreatic Par3. Combined, this study demonstrates how Par3 restrains chronic pancreatitis-induced changes in the pancreas and identifies a potential role for BET inhibitors to attenuate pancreas injury and facilitate regeneration.

Targeting β Cells with Cathelicidin Nanomedicines Improves Insulin Function and Pancreas Regeneration in Type 1 Diabetic Rats.

Type 1 diabetes (T1D) is an incurable condition with an increasing incidence worldwide, in which the hallmark is the autoimmune destruction of pancreatic insulin-producing β cells. Cathelicidin-based peptides have been shown to improve β cell function and neogenesis and may thus be relevant while developing T1D therapeutics. In this work, a cathelicidin-derived peptide, LLKKK18, was loaded in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), surface-functionalized with exenatide toward a GLP-1 receptor, aiming the β cell-targeted delivery of the peptide. The NPs present a mean size of around 100 nm and showed long-term stability, narrow size distribution, and negative ζ-potential (-10 mV). The LLKKK18 association efficiency and loading were 62 and 2.9%, respectively, presenting slow and sustained in vitro release under simulated physiologic fluids. Glucose-stimulated insulin release in the INS-1E cell line was observed in the presence of the peptide. In addition, NPs showed a strong association with β cells from isolated rat islets. After administration to diabetic rats, NPs induced a significant reduction of the hyperglycemic state, an improvement in the pancreatic insulin content, and glucose tolerance. Also remarkable, a considerable increase in the β cell mass in the pancreas was observed. Overall, this novel and versatile nanomedicine showed glucoregulatory ability and can pave the way for the development of a new generation of therapeutic approaches for T1D treatment.

Exocrine pancreas regeneration modifies original pancreas to alleviate diabetes in mouse models

Exocrine pancreas regeneration modifies original pancreas to alleviate diabetes in mouse models

Bone morphogenetic protein-7 attenuates pancreatic damage under diabetic conditions and prevents progression to diabetic nephropathy via inhibition of ferroptosis.

Approximately 30% of diabetic patients develop diabetic nephropathy, a representative microvascular complication. Although the etiological mechanism has not yet been fully elucidated, renal tubular damage by hyperglycemia-induced expression of transforming growth factor-β (TGF-β) is known to be involved. Recently, a new type of cell death by iron metabolism called ferroptosis was reported to be involved in kidney damage in animal models of diabetic nephropathy, which could be induced by TGF-β. Bone morphogenetic protein-7 (BMP7) is a well-known antagonist of TGF-β inhibiting TGF-β-induced fibrosis in many organs. Further, BMP7 has been reported to play a role in the regeneration of pancreatic beta cells in diabetic animal models. We used protein transduction domain (PTD)-fused BMP7 in micelles (mPTD-BMP7) for long-lasting in vivo effects and effective in vitro transduction and secretion. mPTD-BMP7 successfully accelerated the regeneration of diabetic pancreas and impeded progression to diabetic nephropathy. With the administration of mPTD-BMP7, clinical parameters and representative markers of pancreatic damage were alleviated in a mouse model of streptozotocin-induced diabetes. It not only inhibited the downstream genes of TGF-β but also attenuated ferroptosis in the kidney of the diabetic mouse and TGF-β-stimulated rat kidney tubular cells. BMP7 impedes the progression of diabetic nephropathy by inhibiting the canonical TGF-β pathway, attenuating ferroptosis, and helping regenerate diabetic pancreas.

The Role of Krüppel-like Factors in Pancreatic Physiology and Pathophysiology.

Krüppel-like factors (KLFs) belong to the family of transcription factors with three highly conserved zinc finger domains in the C-terminus. They regulate homeostasis, development, and disease progression in many tissues. It has been shown that KLFs play an essential role in the endocrine and exocrine compartments of the pancreas. They are necessary to maintain glucose homeostasis and have been implicated in the development of diabetes. Furthermore, they can be a vital tool in enabling pancreas regeneration and disease modeling. Finally, the KLF family contains proteins that act as tumor suppressors and oncogenes. A subset of members has a biphasic function, being upregulated in the early stages of oncogenesis and stimulating its progression and downregulated in the late stages to allow for tumor dissemination. Here, we describe KLFs' function in pancreatic physiology and pathophysiology.

Combating pancreatic cancer with ovarian cancer cells

With overall five-year survival rate less than 10%, pancreatic cancer (PC) represents the most lethal one in all human cancers. Given that the incidence of PC is still increasing and current cancer treatment strategies are often inefficacious, its therapy is still a huge challenge. Here, we first revealed ovarian serous carcinoma is mostly anti-correlated with pancreatic cancer in gene expression signatures. Based on this observation, we proposed that ovarian cancer cells could defend PC. To confirm this strategy, we first showed that ovarian cancer cell SKOV3 can significantly inhibit the proliferation of pancreatic cancer cell SW1990 when they were co-cultured. We further validated this strategy by an animal model of pancreatic cancer xenografts. The result showed that the injection of SKOV3 significantly inhibits pancreatic cancer xenografts. Moreover, we found that SKOV3 with transgenic African elephant TP53 gene further enhances the therapeutic effect. RNA-sequencing analysis revealed that the ovarian cancer cell treatment strikingly induced changes of genes being involved in pancreas function and phenotype (e.g. enhancing pancreas function, pancreas regeneration, and cell adhesion) but not immune and inflammation-related functions, suggesting that the proposed strategy is different from immunotherapy and could be a novel strategy for cancer treatment.

A57 VANISHING PANCREAS: HIPPO-MEDIATED FOCAL REPLACEMENT OF THE EXOCRINE PANCREAS WITH ADIPOSE TISSUE

Abstract Background The pancreas exhibits remarkable inherent cellular plasticity in response to injury. To prevent inflammatory injury or death, acinar cells can undergo transient acinar-to-ductal metaplasia (ADM) by suspending normal cell functions and adopting characteristics of ductal cells. However, persistent ADM in the setting of chronic pancreatitis predisposes to pancreatic cancer. Less frequently, acinar cells have also been found to undergo acinar-to-adipocyte transdifferentiation, but the mechanisms and clinical significance of this process are largely unknown. Recent studies have identified that the Hippo signaling pathway and its effectors are vital for pancreatic development and function. Purpose YAP is highly expressed in normal pancreatic ducts and transiently in acinar cells undergoing ADM, suggesting a dual role for YAP in (1) the homeostatic maintenance of pancreatic ductal cells, and (2) the regenerative response to injury in acinar cells. However, little is known about the cell type-specific effects of YAP/TAZ on pancreas homeostasis and regeneration. Method We investigated the homeostatic functions of Yap and Taz in the pancreas by conditionally ablating Yap/Taz in both acinar cells and ductal cells using the previously described CluCreERT mouse line. We also established a pancreatic ductal cell-derived organoid system. The efficiency of in vitro Cre recombinase induction was confirmed in Yapfl/fl;Tazfl/fl;CluCre-ERT;LSL-tdTomato (YTKO) ductal organoids. Result(s) We observed severe atrophy and a pancreatitis-like phenotype in the pancreata of YTKO mice following tamoxifen induction. At later time-points, YTKO pancreata were progressively remodeled – the exocrine pancreas was almost entirely replaced by adipose tissue and large hyperplastic ductal structures. We will perform further lineage tracing experiments to determine whether infiltrating adipose cells derive directly from transdifferentiating acinar cells. YTKO pancreatic ductal organoids exhibited disrupted survival and proliferation, evidenced by increased expression of cleaved Caspase3 and decreased EdU incorporation compared to vehicle-treated controls. Conclusion(s) Although some flexibility in cell fate potential is beneficial for the regenerative capacity of the pancreas, dramatic changes in cellular identity can have disastrous consequences. Overall, this study revealed that disruptions in Hippo signaling in the adult murine pancreas led to failure of regeneration and the complete remodeling of the exocrine pancreas, and has shed light on the previously uncharacterized role of Hippo signaling in acinar-to-adipocyte transdifferentiation. The potential contribution of fatty infiltration of the pancreas to the pathogenesis of diabetes mellitus and pancreatic cancer merits further exploration. Please acknowledge all funding agencies by checking the applicable boxes below CIHR, Other Please indicate your source of funding; Fonds de recherche du Quebec - Sante (FRQS) Disclosure of Interest None Declared CELLULAR & MOLECULAR GASTROENTEROLOGY

Delayed Structure – function alterations in Pancreas and Liver of Rodent Diabetic Model treated with Salacia oblonga.

Salacia oblonga (S. oblonga) is a component of several antidiabetic medications in alternative and folklore medicine. An evaluation of the hydroalcoholic root extract of S.oblonga (SOE) on the hepatocellular and pancreatic environment in the diabetic (Streptozotocin) rodent model was designed. SOE was fed in two doses for a period of 16 weeks. Regeneration of endocrine pancreas, significant increase in hepatic and pancreatic Vitamin C, reduced Glutathione (GSH), Protein thiols (PT) and decrease in Malondialdehyde (MDA measured as TBARS) and Carbonyl proteins (CP) were observed on treatment with SOE. Conversely, there was also an increase in alkaline phosphatase (ALP) and gamma glutamyl transferase (GGT). Corroborating the above findings, histopathological examination of the liver and pancreatic tissue showed disrupted architecture in treated rats. It may be suggested that SOE has a sustained hepatic antioxidant effect and improved β-cell structure and function in diabetic rats, but the higher dose was mildly toxic to hepatocytes necessitating an exercise of caution in using SOE for therapy for prolonged periods.

Abstract B032: Sox4-dependent acinar cell plasticity in pancreatic regeneration and cancer initiation

Abstract Gene alterations play a prominent role in driving cancer initiation and progression. Yet, mutations on oncogenes (those genes that promote tumorigenesis) only transform cells under certain cellular contexts. The mechanisms controlling neoplastic transformation (oncogenic competence) are poorly understood in pancreatic ductal adenocarcinoma (PDAC). Our laboratory investigates the interplay of mutations on the Kirsten Rat Sarcoma oncogene (Kras), developmental transcriptional programs, and the tissue microenvironment PDAC initiation. Our data demonstrate that Sox4 is necessary for the specification of cellular states in preinvasive cancer lesions and regulates the characteristics and cellular compositions of the tumor microenvironment in an autochthonous genetic model of PDAC. The pancreas has a remarkable ability to regenerate and recover from acute pancreatitis. In this process, acinar cells repress the expression of genes associated with acinar function and transiently activate a gene program that resembles pancreas progenitors of development. This mechanism, defined as cellular plasticity, alleviates tissue damage, stimulates acinar proliferation, and is necessary for pancreas regeneration. However, it makes the acinar cells competent to malignant transformation mediated by Kras. To investigate SOX4 function in pancreas regeneration and cancer, we used the KCacinar mouse model (Ptf1a-CreER; Kras G12DLSL). After injury, we observed a transient four-fold increase in the expression of SOX4, which correlates with the morphological and molecular evidence of cellular plasticity. KCacinar mice rapidly develop mucinous pancreatic intraepithelial neoplasias (PanINs) after caerulein-induced pancreatitis. Histological analysis KCAcinar Sox4-depleted pancreas (KCSAcinar) reveals a distinct cystic lesion lined by cuboidal or flattened epithelium with large irregular and hyperchromatic nuclei and absence of mucin-producing cells. Mice lacking Sox4 showed a significant reduction in the number of tuft cells. Furthermore, we observed an extensive reduction of the tumor stroma surrounding epithelial acinar-derived lesions in KCSAcinar compared to KC littermates. Next, we perform gene expression analysis of lesions 21 days after the induction of pancreatitis. Principal component analysis clusters the samples according to the genotype. Differential gene expression validated our histopathological analysis and showed a significant reduction in the expression of mucins and tuft cell markers. Cumulative, our data suggest that Sox4 is necessary for the specification of cellular states in the precursor lesions of PDAC, and that the cellular state of the tumor cell of origin determines the characteristics and cellular composition of the tumor microenvironment. Our work will continue to unravel the function of Sox4 in cancer initiation and the interaction of signaling pathways activated in pancreas regeneration with Kras mutations. Citation Format: Jonathan Baldan, Juan Camacho Roda, Charlotte Vestrup Rift, Jane Preuss Hasselby, Patrick Jacquemin, Ilse Rooman, Véronique Lefebvre, Luis Arnes. Sox4-dependent acinar cell plasticity in pancreatic regeneration and cancer initiation [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B032.

Exocrine pancreas regeneration modifies original pancreas to alleviate diabetes in mouse models.

Diabetes is a major public health issue because of its widely epidemic nature and lack of cure. Here, we show that pancreas-derived mesenchymal stem cells (PMSCs) are capable of regenerating exocrine pancreas when implanted into the kidney capsule of mice with streptozotocin (STZ)-induced diabetes. Mechanistically, we found that the regenerated exocrine pancreas elevated interleukin-6 (IL-6) in PMSC implants, which transiently activated tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) to inhibit IL-17, thereby rescuing damaged exocrine pancreas and islet β cells. In addition, we used knockout mouse models to show that global lack of IL-6, TNF-α, or IFN-γ resulted in increased severity of STZ-induced diabetes and resistance to PMSC implantation therapy, confirming the roles of these factors in safeguarding pancreatic β cells. Furthermore, removal of the kidney capsule PMSC implants at 28 days after implantation did not affect the PMSC-initiated therapeutic effect on diabetic mice. This study reveals a previously unknown role of exocrine pancreas regeneration in safeguarding β cells and demonstrates a "soil-rescues-seed" strategy for type 1 diabetes therapy.

Abstract 788: Prrx1 regulates acinar cell plasticity in Kras-driven pancreatic acinar-to-ductal metaplasia

Abstract Introduction: Acinar cells in the adult pancreas demonstrate cellular plasticity and undergo de-differentiation to a progenitor-like cell type with ductal characteristics after injury. This process, termed acinar-to-ductal metaplasia (ADM), is an important feature facilitating pancreas regeneration after injury. In the absence of oncogenic mutations, the ADM lesions resolve and reform the acinar compartment (adaptive ADM). However, in the presence of oncogenic Kras mutations (oncogenic ADM), acinar cells undergo neoplastic transformation after ADM and evolve to pancreatic intraepithelial neoplasia (PanIN), a well-known precursor of pancreatic ductal adenocarcinoma (PDAC). We have characterized the role of Paired-Related Homeobox1 (PRRX1) in adaptive ADM. We demonstrated through our novel conditional Prrx1 knock-out mouse model that loss of Prrx1 abrogated ADM formation. Here we explore the relationship between Prrx1 and mutant Kras on promoting ADM and a pro-ADM microenvironment. Methods: We generated novel Pdx1-Cre;LSLKrasG12D/+;Prrx1fl/fl;Rosa26YFP/YFP (KCY Prrx1 KO) mice, in which mutant Kras is efficiently expressed and Prrx1 is deleted in a pancreas-specific manner. KCY Prrx1 WT and KO mice were sacrificed at 3 months and 5 months for histological analysis. Immunofluorescence (IF) staining for CK19, characterized for the rate of ADM formation and evaluated for F4/80 and SMA. Quantification of ADM regions, F4/80 and SMA was performed through automated cell-counting of immunofluorescence staining (IF). Dissociated acinar cell culture in collagen was utilized for the evaluation of ADM under ex vivo conditions. Results: IF staining revealed that KCY Prrx1 KO mice had fewer ADM lesions compared to Prrx1 WT mice at 3 months. This difference became dramatically apparent at the 5 month timepoint. Additionally, lower areas of fibrosis were identified via H&E staining in KCY Prrx1 KO mice, which was accompanied with lower F4/80 and SMA positivity at both 3 months and 5 months. Ex vivo cultures also demonstrated significant reduction in ADM formation in the context of oncogenic Kras and loss of Prrx1. Conclusions: PRRX1 can influence ADM formation in both a cell-intrinsic and cell-extrinsic manner in the presence of oncogenic KRAS. Our preliminary data suggest Prrx1 facilitates PDAC progression through PanIN formation. We will continue to investigate the mechanisms driving Prrx1-dependent ADM formation. Citation Format: Alina L. Li, Kensuke Sugiura, Kensuke Suzuki, Jason R. Pitarresi, Anna M. Chiarella, Gizem Efe, Rohit Chandwani, Anil K. Rustgi. Prrx1 regulates acinar cell plasticity in Kras-driven pancreatic acinar-to-ductal metaplasia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 788.

Clinical significance of pancreatic ductal metaplasia.

Pancreatic ductal metaplasia (PDM) is the stepwise replacement of differentiated somatic cells with ductal or ductal-like cells in the pancreas. PDM is usually triggered by cellular and environmental insults. PDM development may involve all cell lineages of the pancreas, and acinar cells with the highest plasticity are the major source of PDM. Pancreatic progenitor cells are also involved as cells of origin or transitional intermediates. PDM is heterogeneous at the histological, cellular, and molecular levels and only certain subsets of PDM develop further into pancreatic intraepithelial neoplasia (PanIN) and then pancreatic ductal adenocarcinoma (PDAC). The formation and evolution of PDM is regulated at the cellular and molecular levels through a complex network of signaling pathways. The key molecular mechanisms that drive PDM formation and its progression into PanIN/PDAC remain unclear, but represent key targets for reversing or inhibiting PDM. Alternatively, PDM could be a source of pancreas regeneration, including both exocrine and endocrine components. Cellular aging and apoptosis are obstacles to PDM-to-PanIN progression or pancreas regeneration. Functional identification of the cellular and molecular events driving senescence and apoptosis in PDM and its progression would help not only to restrict the development of PDM into PanIN/PDAC, but may also facilitate pancreatic regeneration. This review systematically assesses recent advances in the understanding of PDM physiology and pathology, with a focus on its implications for enhancing regeneration and prevention of cancer. © 2022 The Pathological Society of Great Britain and Ireland.

Anti-obesity and Anti-diabetic Effect of Ursolic Acid against Streptozotocin/High Fat Induced Obese in Diabetic Rats.

Obesity is occurring due to continue taken high fat diet; this is the fast-growing problem reaching epidemic proportion globally. Ursolic acid altered the abnormal glucose metabolism in diabetic rats. In this experimental protocol, we examine ursolic acid (UA) anti-obesity effect against streptozotocin (STZ) and high-fat diet-induced obesity in rats. Orally administered the ursolic acid (2.5, 5 and 10 mg/kg) dose to the hyperglycemic rats for 8 weeks and estimated the blood glucose level at different time intervals. Biochemical, hepatic, lipid, renal and antioxidant parameters were estimated. Traf-4, Mapk-8, Traf-6 and genes such as Ins-1, ngn-3 and Pdx-1 mRNA expression were estimated using qRT-PCR to scrutinize the molecular mechanism in MAPK downstream JNK cascade and insulin pathway signalling pathways. Ursolic acid significantly (p<0.001) down-regulated the blood glucose level at dose dependent manner. Its also reduced the plasma insulin level, non-essential fatty acid and increased the level of adiponectin as compared to obese control group rats. Ursolic acid treated group rats reduced the level of total cholesterol and triglycerides. Ursolic-acid-treated rats have been shown to decrease oxidative stress in pancreatic tissue by restoring the free radical effect of scavenging, suppress the Traf-6, Mapk-8 and Traf-4 mRNA expression, enhance the expression of Pdx-1, Ins-1 and Ngn-3 and ensure the regeneration of pancreas β cells and therefore pancreas insulin. The current result suggested the anti-obese effect of ursolic acid against high fat diet (HFD) induced obese rats via alteration of insulin and JNK signaling pathway.

Self-renewal equality in pancreas homeostasis, regeneration, and cancer.

Two studies by Lodestijn etal. in Cell Stem Cell and Cell Reports reveal a lack of stem cell hierarchies in acinar cell-derived tissue renewal and host instructed clonogenic growth of pancreatic cancer, thereby elucidating determinants of pancreas regeneration and cancer.

Evaluation of pancreatic regeneration activity of Tephrosia purpurea leaves in rats with streptozotocin-induced diabetes

Background and aimFlavonoid rich plant Tephrosia purpurea (T. purpurea), commonly known as Sarpunkha has been used in traditional systems of medicine to treat diabetes mellitus. However, its effectiveness in promoting regeneration of pancreas in diabetes has not been investigated. Therefore, the present study was undertaken to evaluate pancreatic β-cells regeneration, antioxidant and antihyperlipidemic potentials of T. purpurea leaves extract, its fractions and main constituent Rutin in diabetic rats. Experimental procedureThe leaves extract and its fractions were first screened for acute and sub-chronic antidiabetic activity in a dose range of 250–500 mg/kg orally. Further, fractions with potent antidiabetic activity were screened for pancreatic β-cells regeneration activity using histopathological studies and morphometric analysis, which was followed by estimation of biochemical parameters. Results and conclusionThe most significant antidiabetic, pancreatic regeneration and antihyperlipidemic activity was exhibited by n-butanol soluble fraction of ethanol extract at the dose level of 500 mg/kg. Histopathology revealed that treatment with this fraction improved the β-cell granulation of islets and prevented the β-cells damage which was further confirmed by morphometric analysis. Thus, the present study validated the traditional use of T. purpurea plant in the treatment of diabetes, which might be attributed to pancreatic β-cells regeneration potential of its active constituent Rutin. Taxonomy (classification by EVISE)Traditional Medicine; Metabolic Disorder; Experimental Design; Cell Regeneration and Histopathology.

Superiority of Purple Okra (Abelmoschusesculentus) to Green Okra in Insulin Resistanceand Pancreatic β Cell Improvement in DiabeticRats.

Antidiabetic medicinal plants are increasingly used in the treatment of diabetes as they are generally assumed to pro-duce minimal side effects. Okra is a quercetin-containing plant which can induce pancreas regeneration and has antidiabetic effect. There has been a lot of research that demonstrate that purple okra contains more quercetin than green okra. To demonstrate the advantages of purple okra over green okra on the diabetic markers improvement in diabetic rats. Fifteen male 2-month-old Wistar rats were injected intraperitoneally with 65 mg streptozotocin and 110 mg niacinamide. Their blood glucose levels were measured three days after the injection. The induction of diabetes was deemed successful if the glucose level of the rats got higher than 250 mg/dL, and then such rats were considered diabetic. The diabetic rats were divided into three groups: an acarbose group, a purple okra powder group, and a green okra powder group. The latter two were given, respectively, purple and green okra powder for 28 days. Blood serum was taken to examine the fasting blood glucose, insulin, HOMA-B and GLUT-4 levels. Pancreas was examined histologically for damage using hematoxylin eosin staining. Fasting blood glucose, insulin, HOMA-B, and GLUT-4 levels of diabetic rats that received purple okra powder (p<0.05) were better than those of the rats that received green okra powder. The least damage (p<0.05) to pancreatic beta cells was found in the purple okra powder group. Purple okra is superior to green okra in terms of improving the diabetic markers of rats.

Transcriptional profiles of human islet and exocrine endothelial cells in subjects with or without impaired glucose metabolism

In experimental studies, pancreatic islet microvasculature is essential for islet endocrine function and mass, and islet vascular morphology is altered in diabetic subjects. Even so, almost no information is available concerning human islet microvascular endothelial cell (MVEC) physiology and gene expression. In this study, islets and exocrine pancreatic tissue were acquired from organ donors with normoglycemia or impaired glucose metabolism (IGM) immediately after islet isolation. Following single-cell dissociation, primary islet- and exocrine MVECs were obtained through fluorescence-activated cell sorting (FACS) and transcriptional profiles were generated using AmpliSeq. Multiple gene sets involved in general vascular development and extracellular matrix remodeling were enriched in islet MVEC. In exocrine MVEC samples, multiple enriched gene sets that relate to biosynthesis and biomolecule catabolism were found. No statistically significant enrichment was found in gene sets related to autophagy or endoplasmic reticulum (ER) stress. Although ample differences were found between islet- and exocrine tissue endothelial cells, no differences could be observed between normoglycemic donors and donors with IGM at gene or gene set level. Our data is consistent with active angiogenesis and vascular remodeling in human islets and support the notion of ongoing endocrine pancreas tissue repair and regeneration even in the adult human.