Epithelial-to-Mesenchymal Transition Generates Proliferative Human Islet Precursor Cells

Gershengorn, Marvin C.; Hardikar, Anandwardhan A.; Wei, Chiju; Geras‐Raaka, Elizabeth; Marcus‐Samuels, Bernice; Raaka, Bruce M.

doi:10.1126/science.1101968

Cited by 410 publications

(433 citation statements)

References 27 publications

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“…[19][20][21][22][23] Major interest has been recently raised by the evidence that insulinproducing cells can be obtained following the in vitro expansion of an intermediate mesenchymal proliferating cell population apparently derived from a reversible epithelialmesenchymal transition of pancreatic b-cells. 24, 25 Similar results have been obtained from the exocrine compartment of human pancreas. 26 However, several groups have recently provided evidence, based on cell-lineage tracing experiments in mouse, that mesenchymal cells from pancreatic islets do not originate by an epithelial-mesenchymal transition from b-cells, but may derive from a population of pre-existing connective tissue mesenchymal cells associated with pancreatic epithelial structures.…”

supporting

confidence: 74%

Generation and expansion of multipotent mesenchymal progenitor cells from cultured human pancreatic islets

et al. 2007

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Cellular models and culture conditions for in vitro expansion of insulin-producing cells represent a key element to develop cell therapy for diabetes. Initial evidence that human b-cells could be expanded after undergoing a reversible epithelialmesenchymal transition has been recently negated by genetic lineage tracing studies in mice. Here, we report that culturing human pancreatic islets in the presence of serum resulted in the emergence of a population of nestin-positive cells. These proliferating cells were mainly C-peptide negative, although in the first week in culture, proliferating cells, insulin promoter factor-1 (Ipf-1) positive, were observed. Later passages of islet-derived cells were Ipf-1 negative and displayed a mesenchymal phenotype. These human pancreatic islet-derived mesenchymal (hPIDM) cells were expanded up to 10 14 cells and were able to differentiate toward adipocytes, osteocytes and chondrocytes, similarly to mesenchymal stem/precursor cells. Interestingly, however, under serum-free conditions, hPIDM cells lost the mesenchymal phenotype, formed islet-like clusters (ILCs) and were able to produce and secrete insulin. These data suggest that, although these cells are likely to result from preexisting mesenchymal cells rather than b-cells, hPIDM cells represent a valuable model for further developments toward future replacement therapy in diabetes. Cell Death and Differentiation (2007) 14, 1860-1871; doi:10.1038/sj.cdd.4402199; published online 6 July 2007Type 1 diabetes mellitus is a chronic disease resulting from the selective autoimmune destruction of pancreatic insulinproducing b-cells. Transplantation therapy represents a potential cure for type 1 diabetes mellitus, 1 but is limited by availability of human pancreatic tissue. For this reason, a great effort has been made to develop new methods for generating b-like cells in vitro, 2,3 despite of evidence that cultured b-cells have limited proliferative capacity and reduced insulin production. 4 Several attempts have been made to identify stem/progenitors cells within pancreatic tissue as a potential source for transplantable insulinproducing tissue. Unfortunately, the origin of new b-cells in adult pancreas is not known. Some in vivo studies suggested the presence of pancreatic progenitor cells within islets, 5 whereas others reported that new adult b-cells might rather originate from pre-existing b-cells. 6 Additional studies suggested that progenitor cells may reside within the pancreatic ductal epithelium 2-7 or in the acinar tissue. 8,9 Nevertheless, the exact nature and localization of adult pancreatic stem/ progenitor cells remains controversial [9][10][11][12][13][14][15][16] and their existence in vivo, at least in mice, has recently been questioned. 6 Recent evidence has shown that human embryonic stem cells are able to differentiate into insulin-producing cells in vitro, thus potentially leading to an unlimited source of cells for transplantation. 17 These two authors contributed equally to this work. 5 These two authors share...

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supporting

confidence: 74%

Generation and expansion of multipotent mesenchymal progenitor cells from cultured human pancreatic islets

et al. 2007

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“…Since this work was published a number of groups have repeated and confirmed that a such a precursor cell exists in both rodent and human (Seeberger et al, 2006;Todorov et al, 2006) pancreata. One study would seem to corroborate the work by Dor and colleagues as it showed that human insulin-positive cells undergo an epithelial to mesenchymal transition when kept in culture (Gershengorn et al, 2004). These cells are isolated in a manner similar to that of Peck and co-workers and also undergo long-term culture, followed by a re-differentiation procedure to produce insulin-, Cpeptide-and glucagon-positive clusters.…”

Section: Islet Neogenesis: the Current Hypothesessupporting

confidence: 54%

Mechanisms of action of glucagon-like peptide 1 in the pancreas

Doyle

Egan

2007

Pharmacology & Therapeutics

560

459

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Glucagon-like peptide-1 is a hormone that is encoded in the proglucagon gene. It is mainly produced in enteroendocrine L cells of the gut and is secreted into the blood stream when food containing fat, protein hydrolysate and/or glucose enters the duodenum. Its particular effects on insulin and glucagon secretion have generated a flurry of research activity over the past twenty years culminating in a naturally occurring GLP-1 receptor agonist, exendin-4, now being used to treat type 2 diabetes. GLP-1 engages a specific G-protein coupled receptor that is present in tissues other than the pancreas (brain, kidney, lung, heart, major blood vessels). The most widely studied cell activated by GLP-1 is the insulin-secreting beta cell where its defining action is augmentation of glucose-induced insulin secretion. Upon GLP-1 receptor activation, adenylyl cyclase is activated and cAMP generated, leading, in turn, to cAMP-dependent activation of second messenger pathways, such as the PKA and Epac pathways. As well as short-term effects of enhancing glucose-induced insulin secretion, continuous GLP-1 receptor activation also increases insulin synthesis, and beta cell proliferation and neogenesis. Although these latter effects cannot be currently monitored in humans, there are substantial improvements in glucose tolerance and increases in both first phase and plateau phase insulin secretory responses in type 2 diabetic patients treated with exendin-4. This review we will focus on the effects resulting from GLP-1 receptor activation in islets of Langerhans

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“…While two studies have suggested that under certain conditions pancreatic beta cells can undergo EMT into fibroblast-like cells under culture [32,33], a recent study used lineage tracing to demonstrate that islet-derived fibroblast-like cells were not EMT-derived [34]. The increased pancreatic mesenchyme observed in our Ptch1 mutants resembled an EMT event.…”

Section: Discussionmentioning

confidence: 63%

“…Thus, increased HH signalling results in a reduction of the pancreatic epithelial cells. On the other hand, no studies have investigated the possibility that the increased mesenchyme is formed by an epithelial to mesenchymal transition (EMT) in pancreas of Ptch1 mutants [32][33][34]. To investigate whether the increased mesenchymal cells are indeed the result of an EMT, we performed Cre-lox recombination studies based on in vivo genetic lineage tracing.…”

Section: Resultsmentioning

confidence: 99%

Dose-dependent requirement of patched homologue 1 in mouse pancreatic beta cell mass

et al. 2008

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Aims/hypothesis Ectopic activation of hedgehog (HH) signalling in pancreas induces various abnormal morphogenetic events in the pancreas. This study analysed the dose-dependent requirement of patched homologue 1 (PTCH1), a negative regulator of HH signalling on pancreatic development. Methods We used a recessive spontaneous mutant mouse denoted as mes which carries a mutated Ptch1 resulting in deletion of the most carboxy-terminal cytoplasmic domain of the PTCH1 protein. In this study, we analysed pancreatic morphology in Ptch1 +/+ , Ptch1 +/mes , Ptch1 +/− , Ptch1 mes/mes and Ptch1 −/mes mouse embryos, as well as the islet mass in adult Ptch1 +/+ , Ptch1 +/mes and Ptch1 +/− mice. Results Until embryonic day (E) 12.5, no obvious abnormality of pancreas was observed in any of the Ptch1 mutants. The levels of PDX1 and glucagon were also not evidently different among the mice genotypes studied. Thereafter, morphological abnormalities appeared in the Ptch1 mutant mice. The beta, alpha and exocrine cell masses decreased at E18.5 in parallel with increased HH signalling, with beta cell mass showing the highest sensitivity to HH signalling with a significant decrease even in Ptch1 +/mes mice. Adult Ptch1 +/− mice also showed a significant decrease in beta cell mass compared with wild-type mice. Conclusions/interpretation Our findings indicate that the carboxy-terminal domain of Ptch1 is essential for pancreatic development. In addition, the loss of Ptch1 function decreases both the endocrine and exocrine cell mass in a dose-dependent manner, with beta cells particularly sensitive to changes in HH signalling.

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Epithelial-to-Mesenchymal Transition Generates Proliferative Human Islet Precursor Cells

Cited by 410 publications

References 27 publications

Generation and expansion of multipotent mesenchymal progenitor cells from cultured human pancreatic islets

Generation and expansion of multipotent mesenchymal progenitor cells from cultured human pancreatic islets

Mechanisms of action of glucagon-like peptide 1 in the pancreas

Dose-dependent requirement of patched homologue 1 in mouse pancreatic beta cell mass

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