Generation of Human Islets Through Expansion and Differentiation of Non-islet Pancreatic Cells Discarded (Pancreatic Discard) After Islet Isolation

Todorov, Ivan; Omori, Keiko; Pascual, Michael; Rawson, Jeffery; Nair, Indu; Valiente, Luis; Vuong, Tommy; Matsuda, Takeru; Orr, Chris; Ferreri, Kevin; Smith, Craig V.; Kandeel, Fouad; Mullen, Yoko

doi:10.1097/01.mpa.0000202945.78331.93

Cited by 42 publications

(32 citation statements)

References 47 publications

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“…Whether in the native pancreas they reside in the islet or the exocrine tissue will be unknown until a specific marker has been identified. 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).…”

Section: Islet Neogenesis: the Current Hypothesesmentioning

confidence: 86%

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

Doyle

Egan

2007

Pharmacology & Therapeutics

584

465

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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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Section: Islet Neogenesis: the Current Hypothesesmentioning

confidence: 86%

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

Doyle

Egan

2007

Pharmacology & Therapeutics

584

465

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“…Previous studies have generated functional islets from islet cells themselves (Gershengorn et al 2004, Russ et al 2008, Joglekar et al 2009a as well as exocrine and duct cells from adult human pancreas (Bonner-Weir et al 2000, Todorov et al 2006) from either cadavers or living organ donors. Indeed, bone marrow stem cells can also be subcultured in vitro to more passages, but reduced levels of functional cells were obtained (Wu et al 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Although generation of functional neoislets has been reported from various adult human pancreatic tissues, including pancreatic islets (Lechner et al 2005), nonislet pancreatic cells, discarded after islet isolation (Todorov et al 2006), and exocrine cells (Rapoport et al 2009), it remains to be determined whether these sources provide the amount of neoislets required for in vivo regeneration therapy for diabetic patients.…”

Section: Introductionmentioning

confidence: 99%

Alleviation of hyperglycemia in diabetic rats by intraportal injection of insulin-producing cells generated from surgically resected human pancreatic tissue

Shyu

Wang

Shyr

et al. 2010

Journal of Endocrinology

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Although islet transplantation holds promise for the treatment of diabetes, the scarcity of donor tissue remains a major drawback. The aim of this study is to generate insulinproducing cells from adult human pancreatic cells isolated from surgically resected pancreatic tissue. To isolate pancreatic endocrine precursor cells from 57 surgically resected pancreases, the cells were cultured and propagated in conditioned medium after which they were differentiated in Matrigel. The resultant cells were characterized using morphology, immunofluorescent studies, expression of differentiated pancreatic islet-specific genes using quantitative reverse transcription-PCR, and glucose-induced insulin secretion through analysis of C-peptide secretion. The relationships between propagation of insulin-producing cells and clinical variables of the donor were also analyzed. Finally, insulin-producing cell function was examined in streptozotocin-induced diabetic rats. Pancreatic endocrine precursor cells were successfully cultured; insulin-producing cells cultured from soft pancreas parenchyma had a significantly higher success rate. Morphological examination revealed islet-like cluster formation upon transfer to Matrigel. The presence of the neural stem cell marker nestin, duct cell marker cytokeratin 19, and endocrine cell markers C-peptide and pancreatic and duodenal homeobox 1, was also observed. In addition, glucose-stimulated C-peptide release was significantly increased in the insulinproducing cells. Furthermore, in diabetic rats, transplantation of insulin-producing cells reduced hyperglycemia. Isolated pancreatic endocrine precursor cells from surgically resected pancreatic tissue differentiated into insulin-producing cells and showed characteristics of functional endocrine cells. Thus, surgically resected pancreatic tissue may represent an alternative source of functional insulin-producing cells.

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“…To test if the interaction with VECs would enhance endocrinal differentiation in vitro, we co-cultured the VECs and NEECs to form a spherical tissue complex in a suspension culture, the method previously used for generating islet-like tissues and known to increase their insulin-secretion ability [27,28]. Cells dissociated from culture containers were swirl-incubated in a culture medium to promote direct homotypic and heterotypic cell-to-cell contacts.…”

Section: Discussionmentioning

confidence: 99%

Tissue Complex of Adult Pancreatic Duct and Vascular Endothelial Cells Promotes In Vitro Differentiation into Insulin-Producing Cells

Kanamune¹

2015

SRDT

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Generation of Human Islets Through Expansion and Differentiation of Non-islet Pancreatic Cells Discarded (Pancreatic Discard) After Islet Isolation

Abstract: Using the specified culture methods, non-islet pancreas cells can generate cell clusters resembling islets. These ICCs, obtained from fractions of the pancreas that are otherwise discarded, continue to differentiate after transplantation to become mature islets.

Cited by 42 publications

References 47 publications

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

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

Alleviation of hyperglycemia in diabetic rats by intraportal injection of insulin-producing cells generated from surgically resected human pancreatic tissue

Tissue Complex of Adult Pancreatic Duct and Vascular Endothelial Cells Promotes In Vitro Differentiation into Insulin-Producing Cells

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