Redifferentiation of insulin-secreting cells after in vitro expansion of adult human pancreatic islet tissue

Lechner, Andreas; Nolan, Anna L.; Blacken, Robyn A.; Habener, Joel F.

doi:10.1016/j.bbrc.2004.12.043

Cited by 103 publications

(75 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: 78%

“…Fibroblast-like cells emerging from pancreatic islets have been shown to be able to differentiate into insulin-expressing cells. [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] To evaluate the ability of hPIDM cells to differentiate into a pancreatic endocrine phenotype, cells were cultured for 21 days in a medium for endocrine differentiation. Under these conditions, cells formed clusters that remained adherent to culture plates for the first week, but afterward detached acquiring an isletlike morphology (Figure 6a).…”

Section: Resultsmentioning

confidence: 99%

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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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confidence: 78%

Section: Resultsmentioning

confidence: 99%

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

et al. 2007

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“…Interestingly, a similar effect has been observed in human islet cell culture in vitro. Lechner A et al reported that culturing of human islet cells in a monolayer leads to the loss of insulin expression and that re-aggregation of the expanded islet cells was subsequently required to increase insulin expression in vitro [17].…”

Section: Discussionmentioning

confidence: 99%

In vitro derivation of functional insulin-producing cells from human embryonic stem cells

et al. 2007

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The capacity for self-renewal and differentiation of human embryonic stem (ES) cells makes them a potential source for generation of pancreatic beta cells for treating type I diabetes mellitus. Here, we report a newly developed and effective method, carried out in a serum-free system, which induced human ES cells to differentiate into insulin-producing cells. Activin A was used in the initial stage to induce definitive endoderm differentiation from human ES cells, as detected by the expression of the definitive endoderm markers Sox17 and Brachyury. Further, all-trans retinoic acid (RA) was used to promote pancreatic differentiation, as indicated by the expression of the early pancreatic transcription factors pdx1 and hlxb9. After maturation in DMEM/F12 serum-free medium with bFGF and nicotinamide, the differentiated cells expressed islet specific markers such as C-peptide, insulin, glucagon and glut2. The percentage of C-peptide-positive cells exceeded 15%. The secretion of insulin and C-peptide by these cells corresponded to the variations in glucose levels. When transplanted into renal capsules of Streptozotocin (STZ)-treated nude mice, these differentiated human ES cells survived and maintained the expression of beta cell marker genes, including C-peptide, pdx1, glucokinase, nkx6.1, IAPP, pax6 and Tcf1. Thirty percent of the transplanted nude mice exhibited apparent restoration of stable euglycemia; and the corrected phenotype was sustained for more than six weeks. Our new method provides a promising in vitro differentiation model for studying the mechanisms of human pancreas development and illustrates the potential of using human ES cells for the treatment of type I diabetes mellitus.

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“…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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Redifferentiation of insulin-secreting cells after in vitro expansion of adult human pancreatic islet tissue

Cited by 103 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

In vitro derivation of functional insulin-producing cells from human embryonic stem cells

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

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