Role of Tyrosine Kinase Signaling for β-Cell Replication and Survival

Welsh, Michael; Annerén, Cecilia; Lindholm, Cecilia; Křı́ž, Vı́tězslav; Öberg-Welsh, Charlotte

doi:10.1517/03009734000000052

Cited by 17 publications

(18 citation statements)

References 24 publications

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“…Our previous findings, in agreement with those of others, confirm that the early postnatal rat pancreas retains a population of c-Kit-positive precursor cells within the islets (Oberg-Welsh & Welsh 1996, Welsh et al 2000, Rachdi et al 2001, Yashpal et al 2004. Islets cultured on type I collagen matrix rapidly adhered to the matrix, and spread to form a monolayer of cytokeratin-positive epithelial cells.…”

Section: Discussionsupporting

confidence: 92%

“…c-Kit expression in the pancreas has been previously described in the pancreatic ducts (Oberg-Welsh & Welsh 1996), and it is implicated in the development, function and survival of the islets of Langerhans and, more importantly, in -cell survival (Welsh et al 2000). Rachdi et al reported that Kit mRNA is present in fetal and adult rat islets, and is specifically transcribed in cells (Rachdi et al 2001), as confirmed by our in vivo study on the developing rat pancreas.…”

Section: Introductionsupporting

confidence: 86%

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Phenotypic analysis of c-Kit expression in epithelial monolayers derived from postnatal rat pancreatic islets

Wang¹,

Li²,

Yashpal³

2004

Journal of Endocrinology

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The limitation of available islets for transplantation is a major obstacle for the treatment of diabetes through islet therapy. However, islet monolayers expanded ex vivo may provide a source of progenitor cells and a model to help understand islet development from precursor cell types. The existence of progenitor cells within the islets is highly likely, yet, to date, no fully defined or characterized postnatal stem cell has been isolated, expanded or marked. Our study evaluates the expression of progenitor markers, including the haematopoietic stem cell marker c-Kit, in epithelial monolayers derived from postnatal rat islets through immunofluorescence and RT-PCR, and the ability of precursor-rich monolayers to reform islet-like structures. Islets formed confluent monolayers when cultured on a type I collagen gel which lacked endocrine phenotypes but were positive for cytokeratin 20 and contained an increased proportion of proliferating c-Kitexpressing cells, with the proportion reaching a maximum of 45 6% at 8 weeks of culture. Evaluation of transcription factors at the mRNA level revealed constant PDX-1, ngn3 and Pax4 expression, while undifferentiated cell markers, such as Oct4 and -fetoprotein, were also detected frequently after 4 weeks of culture. Changing the extracellular matrix protein to laminin-rich Matrigel, the monolayers re-formed islet-like clusters that secreted insulin in a glucose-responsive fashion. Our data show that islets can be expanded ex vivo to form epithelial monolayers with rich undifferentiating cell populations that are characterized by cells expressing the progenitor markers. These monolayers are capable of extensive proliferation and retain plasticity to form new islet cells, and c-Kitexpressing cells may play an important role in new islet cluster formation.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionsupporting

confidence: 86%

Phenotypic analysis of c-Kit expression in epithelial monolayers derived from postnatal rat pancreatic islets

Wang¹,

Li²,

Yashpal³

2004

Journal of Endocrinology

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“…Experimental studies 27 localized the c-kit protein to ducts of the fetal rat pancreas and to normal and hyperplastic ducts of the normal pancreas. 28 Welsh et al 29 postulated that tyrosine kinases may play a role in beta-cell replication, differentiation (neoformation) and survival, as ducts are thought to harbor beta-cell precursor cells. The CD34 and CD117-positive stroma cells in our two cases seem to be matrixproducing cells.…”

Section: Resultsmentioning

confidence: 99%

Cellular hamartoma resembling gastrointestinal stromal tumor: a solid tumor of the pancreas expressing c-kit (CD117)

et al. 2005

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Solid tumors of the pancreas are usually neoplastic. We report on two adult patients, each with a solid tumor of the pancreas that presented with an unusual histology and seemed to follow a benign course. The tumors, one located in the body and one in the tail, were well demarcated and composed of irregularly arranged but welldifferentiated acini and small intralobular and interlobular ducts embedded in predominantly hypocellular fibrotic tissue that contained fascicles of cytologically bland spindle cells. Islets were lacking, but immunohistochemical staining for chromogranin A and insulin revealed individual scattered insulin-producing cells distributed between acinar and ductal cells. The spindle cell component tissue showed coexpression of CD34, c-kit (CD117) and bcl-2. The follow-up (2 and 4 years) of the patients was uneventful. We propose to designate the tumors as 'cellular hamartoma resembling gastrointestinal stromal tumor.' Modern Pathology ( Keywords: pancreatic tumor; hamartoma; c-kit; CD34; bcl-2; differential diagnosis Well-demarcated tumor-like lesions in the pancreas are uncommon. They have been described under the term pseudotumor 1 or inflammatory pseudotumor. 2 Recently, we described a tumorous lesion that we termed pancreatic solid and cystic hamartoma. 3 Here we report on two further solid pancreatic tumors that have features in common with both hamartomas and gastrointestinal stromal tumors. Patients, materials and methodsThe cases were collected from the consultation files of the Department of Pathology of the University of Kiel, to which they had been submitted by the Department of Pathology in Dinslaken, Germany (case 1), and the Department of Pathology of the University of Coimbra, Portugal (case 2).In the first case, a 51-year-old man without clinical symptoms had a routine check-up, during which a mass, 3 cm in diameter, was detected by ultrasonography in the tail of the pancreas next to the splenic artery. This finding was confirmed by endosonography and CT. Laboratory tests were normal. As a result of the unclear nature of the tumor, abdominal surgery was performed with resection of the tumor.In the second case, a 54-year-old woman with slight abdominal discomfort was examined by ultrasonography, which revealed a well-demarcated tumor, 2 cm in diameter, in the body of the pancreas. A left-sided pancreatic resection was performed to remove the tumor. Both patients had an uncomplicated postoperative course and so far (2 and 4 years, respectively) have relapse-free follow-up.Representative 4 mm sections of formalin-fixed, paraffin-embedded tissue from both specimens were stained with hematoxylin and eosin (H&E) and periodic acid-Schiff. Immunohistochemical staining was performed using the standard avidinbiotin method against following antibodies: cytokeratin 8 (CAM 5

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“…Furthermore, W and Sl mutant mice display increased germ cell apoptosis, with a corresponding degree of sterility [41]. More importantly, accumulating evidence suggests that c-Kit expression is also linked to the development of the endocrine pancreas, as well as to beta cell survival and function [11,12,[42][43][44][45][46][47][48][49][50][51][52][53].…”

Section: C-kit Function In Organ Developmentmentioning

confidence: 99%

A survival Kit for pancreatic beta cells: stem cell factor and c-Kit receptor tyrosine kinase

et al. 2015

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The interactions between c-Kit and its ligand, stem cell factor (SCF), play an important role in haematopoiesis, pigmentation and gametogenesis. c-Kit is also found in the pancreas, and recent studies have revealed that c-Kit marks a subpopulation of highly proliferative pancreatic endocrine cells that may harbour islet precursors. c-Kit governs and maintains pancreatic endocrine cell maturation and function via multiple signalling pathways. In this review we address the importance of c-Kit signalling within the pancreas, including its profound role in islet morphogenesis, islet vascularisation, and beta cell survival and function. We also discuss the impact of c-Kit signalling in pancreatic disease and the use of c-Kit as a potential target for the development of cell-based and novel drug therapies in the treatment of diabetes.

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Role of Tyrosine Kinase Signaling for β-Cell Replication and Survival

Cited by 17 publications

References 24 publications

Phenotypic analysis of c-Kit expression in epithelial monolayers derived from postnatal rat pancreatic islets

Phenotypic analysis of c-Kit expression in epithelial monolayers derived from postnatal rat pancreatic islets

Cellular hamartoma resembling gastrointestinal stromal tumor: a solid tumor of the pancreas expressing c-kit (CD117)

A survival Kit for pancreatic beta cells: stem cell factor and c-Kit receptor tyrosine kinase

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