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

Abstract

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.

Stem Cell Therapy for Islet Regeneration

“…Moreover, 9/19 mice transplanted with progenitor cells, and 2/4 mice transplanted with IPCs, secreted C-peptide in response to glucose (Zang et al, 2010). Allotransplantation of IPCs differentiated from islet progenitor cells produced similar results (Shyu et al 2011). In this study, progenitor cells cultured in matrigel differentiated into IPCs following transplantation into diabetic mice.…”

“…Other studies report the successful use of transgenesis to differentiate MSCs into IPCs, or upregulation of genes (mainly PDX-1 or betacellulin) related to signalling pathways that trigger this process (Karnieli et al, 2007;Li et al, 2007;Li et al, 2008;Hisanaga et al, 2008;Limbert and Seufert., 2009;Yuan et al, 2010;Paz et al, 2011). Moreover, coating the tissue culture flasks with substrates such as fibronectin or laminin can also induce MSCs to differentiate into IPCS (Moriscot et al, 2005;Chang et al, 2008;Lin et al, 2010;Lin et al, 2011).…”

“…Many different types of stem cells have been tested using different methods. Cells can be grafted underneath the kidney capsule (Rackham et al, 2011;Figliuzzi et al, 2009;Ito et al, 2010;Kodama et al, 2009;Kodama et al, 2008;Zhang et al, 2010;Ohmura et al, 2010;Xiao et al, 2008;Berman et al, 2010), delivered via intra-peritoneal injection (Boroujeni et al, 2011;Chandra et al, 2009;Koya et al, 2008;Shao et al, 2011;Phuc et al, 2011; or intra-portally (Shyu et al, 2011;Trivedi et al, 2008;Wu et al, 2007;Longoni et al, 2010;Itakura et al, 2007), grafted into the liver (Chao et al, 2008;Zhu et al, 2009;Xu et al, 2007;Wang et al, 2010) or injected into the tail vein (Dinarvand et al, 2010;Koblas et al, 2009;Kajiyama et al, 2010;Jurewicz et al, 2010) (Fig. 3).…”

Hyperglycemia can delay left ventricular dysfunction but not autonomic damage after myocardial infarction in rodents

“…For this reason, new therapeutic strategies have been studied in diabetes management. Shyu et al, [38] described the isolation of pancreatic endocrine precursor cells, from adult human pancreatic tissue, and the redifferentiation of insulin-secreting β-like cells from in vitro-cultured insulin-producing cell precursors. These data emphasize that surgically resected pancreatic tissue may represent an alternative source of functional insulin-producing cells and to minimize the cardiovascular dysfunctions of diabetes.…”

Endodermal progenitor cells isolated from mouse pancreas

“…However, the amount of insulin produced by these cells was much lower than what is produced by a naturally occurring islet-derived β-cell. It has also been shown that endocrine precursors can be derived from surgically resected portions of human pancreas and that islets themselves contain a population of mesenchymal stem cells [41,42]. Recently published data bolsters the idea of a precursor cell in pancreas citing the existence of insulin positive multipotent stem cells that give rise to pancreatic and neural lineages and that ameliorate diabetes in animal models [43].…”