Regeneration and Repair of the Exocrine Pancreas

Murtaugh, L. Charles; Keefe, Matthew D.

doi:10.1146/annurev-physiol-021014-071727

Cited by 162 publications

(184 citation statements)

References 117 publications

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“…Pancreatic injury also triggers a counteractive regenerative response that restores digestive enzyme-producing acinar cells. This response entails the proliferation of residual acinar tissue and acinar to ductal metaplasia (ADM), a process in which acinar cells dedifferentiate to become ductal progenitors, which eventually restore acinar tissue mass and function (35,36). Atg7 Δpan 12-wk-old pancreata exhibited up-regulation of several pancreatic progenitor and ductal markers, including Ptf1, Sox9, CK19, and Pdx1, as well as the Notch target genes Hes1 and Nestin (Fig.…”

Section: Loss Of Atg7 Results In Er Stress and Mitochondrial Dysfunctmentioning

confidence: 99%

Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress

Antonucci

Fagman

Kim

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

201

182

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Pancreatic acinar cells possess very high protein synthetic rates as they need to produce and secrete large amounts of digestive enzymes. Acinar cell damage and dysfunction cause malnutrition and pancreatitis, and inflammation of the exocrine pancreas that promotes development of pancreatic ductal adenocarcinoma (PDAC), a deadly pancreatic neoplasm. The cellular and molecular mechanisms that maintain acinar cell function and whose dysregulation can lead to tissue damage and chronic pancreatitis are poorly understood. It was suggested that autophagy, the principal cellular degradative pathway, is impaired in pancreatitis, but it is unknown whether impaired autophagy is a cause or a consequence of pancreatitis. To address this question, we generated Atg7 Δpan mice that lack the essential autophagy-related protein 7 (ATG7) in pancreatic epithelial cells. Atg7 Δpan mice exhibit severe acinar cell degeneration, leading to pancreatic inflammation and extensive fibrosis. Whereas ATG7 loss leads to the expected decrease in autophagic flux, it also results in endoplasmic reticulum (ER) stress, accumulation of dysfunctional mitochondria, oxidative stress, activation of AMPK, and a marked decrease in protein synthetic capacity that is accompanied by loss of rough ER. Atg7 Δpan mice also exhibit spontaneous activation of regenerative mechanisms that initiate acinar-to-ductal metaplasia (ADM), a process that replaces damaged acinar cells with duct-like structures.T he pancreatic acinar cell is responsible for production and secretion of numerous digestive enzymes, including amylase, lipase, and various proteases. To cope with the high daily demand for these enzymes, the acinar cell possesses one of the highest protein biosynthetic rates of all cells, together with an extensive rough endoplasmic reticulum (RER) network (1). Due to its high protein synthetic rates, the acinar cell is prone to the accumulation of misfolded proteins and subsequent induction of ER stress (2, 3). ER stress was suggested to be involved in the pathogenesis of pancreatitis, a potentially fatal inflammatory disease of the exocrine pancreas (2, 4). By progressing from acute (sudden onset; duration <6 mo), to recurrent acute (>1 episode of acute pancreatitis), and chronic (duration >6 mo) disease (5), pancreatitis increases the risk of pancreatic ductal adenocarcinoma (PDAC), the fourth deadliest cancer worldwide, with a median survival of 6 mo (6). The molecular mechanisms mediating the progression of pancreatitis from acinar cell damage and inflammation to formation of pancreatic intraepithelial neoplasia (PanIN) and PDAC are not fully understood. Recent studies suggest that in addition to ER stress, insufficient autophagy also contributes to development of pancreatitis (7).Autophagy is an evolutionarily conserved, catabolic quality control process that maintains cellular homeostasis by degrading damaged organelles, misfolded protein aggregates, and foreign organisms (8). Autophagy is also important for generation of amino acids and other building blo...

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Section: Loss Of Atg7 Results In Er Stress and Mitochondrial Dysfunctmentioning

confidence: 99%

Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress

Antonucci

Fagman

Kim

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

201

182

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“…Other authors have reported an association with ampullary adenocarcinoma and intraductal papillary mucinous neoplasm (IPMN) (6,26). There have also been reports of an increase in the size of the remnant pancreas and recurrent acute pancreatitis as a form of presentation (48).…”

Section: Discussionmentioning

confidence: 99%

“…In experimental models of acute pancreatitis and in partial resections of the pancreas, regeneration of the pancreas has been reported in mice and children with nesidioblastosis, but never in adults (41,48,49). In the regenerative response of the pancreas, the presence of acinar-ductal metaplasia has been reported where there is an upregulation of ductal markers such as CK19 and SOX9.…”

Section: Discussionmentioning

confidence: 99%

Agenesis of the dorsal pancreas: systematic review of a clinical challenge

Cienfuegos¹,

Rotellar²,

Salguero³

et al. 2016

Rev Esp Enferm Dig

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Background: Agenesis of the dorsal pancreas is a rare malformation. Since 1911 and until 2008, 53 cases have been reported. Several authors have recently described the association of this anomaly with neoplasia of the ventral pancreas, thus we performed a systematic review of the literature from 2008 to 2015.Methods: A systematic review of the Medline and ISI Web of Science Databases from 2008 until 2015 was carried out, and 30 articles which met the inclusion criteria were identified that included a total of 53 patients: 7 children and 46 adults.Conclusions: Although dorsal pancreatic agenesis is a rare malformation, given its association with non-alcoholic pancreatitis and neoplasia of the residual pancreas, physicians should maintain an expectant attitude.

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“…Ces limites ont réorienté les investigations vers des stratégies de différenciation in situ, sans recours à l'isolement et à la culture cellulaires. Au-delà de la controverse sur les capacités des cellules acinaires à produire spontanément de nouvelles cellules β lors de pancréatecto-mies ou autres lésions pancréatiques [42], il est admis que ces cellules sont capables de régénérer le pancréas exocrine [43]. Elles sont considérées à ce titre comme des progéniteurs facultatifs.…”

Section: Cellules Acinairesunclassified

La thérapie cellulaire du diabète

Lysy

2016

Med Sci (Paris)

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> La poss ibilité de remplacer des cellules β déficientes par de nouvelles cellules insulinosécrétantes chez le patient diabétique est démontrée par le succès de la transplantation d'îlots pancréatiques. Le manque de donneurs cadavériques a stimulé la recherche de sources alternatives de cellules β dont le palmarès est dominé par les cellules souches pluripotentes humaines pouvant acquérir des caractéristiques quasiment identiques à celles des cellules β et rétablir l'équilibre glycémique de souris diabétiques. Néanmoins, elles comportent un risque carcinogénique actuellement inévitable. Le pancréas adulte héberge des compartiments cellulaires aux capacités de transdifférenciation établies pouvant être exploitées pharmacologiquement in situ ou via des phases d'expansion en culture. Cette revue s'intéresse aux nouveaux développements concernant la thérapie cellulaire du diabète. < vie permettent de prévenir 60 % des DT2, il n'y a, à ce jour, aucune straté-gie de prévention du DT1 et les traitements actuels ne permettent pas d'atteindre les objectifs thérapeutiques tels que révélés par le dosage de l'hémoglobine glyquée (ou glycatée) (HbA1 C ) 2 [1]. Le DT1 est donc la cible des stratégies développées pour le remplacement des cellules β qui ont vu le jour en 1966 à Minneapolis avec la première greffe de pancréas humain combinée à une greffe de rein [2]. Après plus de 47 000 greffes d'organe (pancréas associé au rein ou pancréas seul), la technique a été nettement raffinée. Elle permet actuellement une survie des greffons d'environ 85 % à 1 an post-chirurgie [3], ce qui en fait une option thérapeutique pour des patients diabétiques en insuffisance rénale [4]. Cette technique n'est malgré tout pas généralisable étant donnés les degrés de morbidité et de mortalité associés au geste chirurgical (75 % de survie à 10 ans), la nécessité d'une immunosuppression à vie, et le manque de donneurs d'organe. Ces difficultés ont stimulé la recherche pour une thérapie cellulaire du diabète fondée sur des sources cellulaires variées comme les îlots pancréatiques 3 , les cellules souches pluripotentes ou les cellules somatiques adultes du pancréas. Transplantation des îlots pancréatiquesLa transplantation des îlots de Langerhans du pancréas humain s'est développée dans les années 1970, comme une alternative moins invasive à la greffe de pancréas entier. Cette technique a bénéficié de la 2 L'hémoglobine glyquée est une forme d'hémoglobine ayant subi une glycation, c'est-à-dire une addition non enzymatique de sucre sur la protéine. C'est un marqueur de la glycémie. 3 Les îlots pancréatiques, ou îlots de Langerhans sont formés de cellules endocrines capables de synthéti-ser l'insuline, le glucagon, la somatostatine et le polypeptide pancréatique.

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Regeneration and Repair of the Exocrine Pancreas

Cited by 162 publications

References 117 publications

Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress

Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress

Agenesis of the dorsal pancreas: systematic review of a clinical challenge

La thérapie cellulaire du diabète

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