Article

β-Cell Generation: Can Rodent Studies Be Translated to Humans?

Department of Nephrology, Leiden University Medical Center, Postal Zone C3-P, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
Journal of Transplantation 10/2011; 2011:892453. DOI: 10.1155/2011/892453
Source: PubMed

ABSTRACT

β-cell replacement by allogeneic islet transplantation is a promising approach for patients with type 1 diabetes, but the shortage of organ donors requires new sources of β cells. Islet regeneration in vivo and generation of β-cells ex vivo followed by transplantation represent attractive therapeutic alternatives to restore the β-cell mass. In this paper, we discuss different postnatal cell types that have been envisaged as potential sources for future β-cell replacement therapy. The ultimate goal being translation to the clinic, a particular attention is given to the discrepancies between findings from studies performed in rodents (both ex vivo on primary cells and in vivo on animal models), when compared with clinical data and studies performed on human cells.

Download full-text

Full-text

Available from: Johanne Ellenbroek
  • Source
    • "This has led to a large number of clinical studies involving administration of hMSCs. However, only few reports demonstrated robust differentiation of human MSC into insulin-producing cells [17]. Experiments performed in our laboratory employing lentiviral vectors expressing key master transcription factors to force differentiation of hMSC into insulin-producing cells did not yield an efficient protocol for the formation of endocrine-pancreatic cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Viral gene carriers are being widely used as gene transfer systems in (trans)differentiation and reprogramming strategies. Forced expression of key regulators of pancreatic differentiation in stem cells, liver cells, pancreatic duct cells, or cells from the exocrine pancreas, can lead to the initiation of endocrine pancreatic differentiation. While several viral vector systems have been employed in such studies, the results reported with adenovirus vectors have been the most promising in vitro and in vivo. In this study, we examined whether the viral vector system itself could impact the differentiation capacity of human bone-marrow derived mesenchymal stem cells (hMSCs) toward the endocrine lineage. Lentivirus-mediated expression of Pdx-1, Ngn-3, and Maf-A alone or in combination does not lead to robust expression of any of the endocrine hormones (i.e. insulin, glucagon and somatostatin) in hMSCs. Remarkably, subsequent transduction of these genetically modified cells with an irrelevant early region 1 (E1)-deleted adenoviral vector potentiates the differentiation stimulus and promotes glucagon gene expression in hMSCs by affecting the chromatin structure. This adenovirus stimulation was observed upon infection with an E1-deleted adenovirus vector, but not after exposure to helper-dependent adenovirus vectors, pointing at the involvement of genes retained in the E1-deleted adenovirus vector in this phenomenon. Lentivirus mediated expression of the adenovirus E4-ORF3 mimics the adenovirus effect. From these data we conclude that E1-deleted adenoviral vectors are not inert gene-transfer vectors and contribute to the modulation of the cellular differentiation pathways.
    Full-text · Article · Oct 2012 · PLoS ONE
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Revascularization of grafts is one of the important key factors for the success of islet transplantation. After partial hepatectomy, many growth factors such as hepatocyte growth factor and vascular endothelial growth factor are increased in the remnant liver. These growth factors have properties that promote angiogenesis. This might be an optimal environment for revascularization of islets transplanted intraportally. To verify this hypothesis, syngeneic islets (330 per recipient) were transplanted into the right hepatic lobes of streptozotocin-induced diabetic Balb/c mice with (hepatectomy group) or without (control group) left liver resection. Blood glucose was monitored for 28 d after transplantation. Glucose tolerance test was performed on post-operative day (POD) 30, and histological assessments were performed on POD 7 and 30 respectively. Analysis revealed that 36.7% of the control and 90.0% of the hepatectomy mice attained normoglycemia during the observation period (*p = 0.0142). Glucose tolerance was improved in the hepatectomy group (Area under the curve of intraperitoneal glucose tolerance tests on POD 30, Control; 47,700 ± 5,890 min*mg/dl, Hepatectomy; 26,000 ± 2,060 min*mg/dl: **p = 0.00314). Revascularization of grafted islets was more pronounced in the hepatectomy group (Vessel number per islet area on POD 7, Control; 3.20 ± 0.463 × 10 (-4) /µm ( 2) , Hepatectomy; 7.08 ± 0.513 × 10 (-4) /µm ( 2) : **p < 0.01). In the present study, partial hepatectomy (30%) improved the outcome of intraportal islet transplantation. Revascularization of islets transplanted into the liver may have been promoted by the induction of liver regeneration.
    Preview · Article · Mar 2012 · Islets
  • [Show abstract] [Hide abstract]
    ABSTRACT: Overnutrition during pregnancy and lactation lend increasing support to the development of obesity and several chronic diseases in adulthood such as type 2 diabetes mellitus, which leads to beta-cell dysfunction and insulin resistance. In this work, we aimed to study the effects of early life overnutrition on the development of obesity, analyzing the morphological changes, expression of TNF-α, and also the stem cell marker CD133 in the pancreatic islets of young and adult mice. Overnutrition during lactation phase was used as an experimental model to induce obesity. The animals were analyzed at 28 and 150 days of age, when pancreata were collected for histological, ultrastructural and western blotting analysis. The results showed that islet hypertrophy is established in obese groups at day 28 and remained until adulthood. CD133+ cells were observed as small cells within pancreatic islets in both control and obese young mice. However, at day 150, these cells were observed only in the islet peripheries and near ducts of the obese group. Furthermore, TNF-α expression in pancreatic islets was increased in both young and adult obese groups when compared to control groups. This work shows interesting data about CD133 receptor and TNF-α roles in the pancreas during obesity development.
    No preview · Article · Apr 2012 · Tissue and Cell
Show more