Human islet graft function in NOD-SCID mice predicts clinical response in islet transplant recipients

Gaber, A. Osama; Fraga, Daniel; Kotb, Malak; Lo, Agnes; Sabek, Omaima; Latif, Kashif

doi:10.1016/j.transproceed.2004.04.055

Cited by 30 publications

(26 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The choice of 12 ng/ml to define transplant success using the scatter plot of quantiles was susceptible to error. We considered defining transplant success as C-peptide Ͼ1.5 ng/ml, which was 2 standard deviations above background levels for the C-peptide assay (29,30,36). However, in our study, C-peptide was lower than 1.5 ng/ml in response to the IPGTT in only one case.…”

Section: Discussionmentioning

confidence: 70%

“…In these cases, even islets that are viable may not survive after transplantation. To minimizes these effects, a non-diabetic mouse model, the NOD/SCID, was used as the transplant recipient (29,30,36). Because we are not using diabetic mice, there is not a natural clinical threshold that would be based on blood glucose levels with which to use as criteria to evaluate the predictive value of the assays.…”

Section: Discussionmentioning

confidence: 99%

“…The protocol has been described previously (29,30). For each assessment of human islets, batches of 1000 and 2000 IE were transplanted under the left renal capsule of 5 mice for each quantity of islets for a total of 10 mice transplanted.…”

Section: Transplantation Of Human Islets Into Nod-scid Micementioning

confidence: 99%

See 2 more Smart Citations

Glucose Stimulation of Cytochrome C Reduction and Oxygen Consumption as Assessment of Human Islet Quality

Sweet¹,

Gilbert²,

Jensen³

et al. 2005

Transplantation

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Glucose Stimulation of Cytochrome C Reduction and Oxygen Consumption as Assessment of Human Islet Quality

Sweet¹,

Gilbert²,

Jensen³

et al. 2005

Transplantation

View full text Add to dashboard Cite

show abstract

“…Moreover, in one of the mice cotransplanted with hESCs and mouse dorsal pancreas, human C-peptide was detected at levels (1.81 ng/ml) corresponding to normal serum C-peptide levels in nonfasted humans (ϳ2 ng/ml) (47,48). Notably, the graft from this individual contained the highest number of insulin ϩ clusters (data not shown).…”

Section: Fig 6 Hesc-derived Insulinmentioning

confidence: 92%

Signals From the Embryonic Mouse Pancreas Induce Differentiation of Human Embryonic Stem Cells Into Insulin-Producing β-Cell–Like Cells

Brolén

Heins²,

Edsbagge³

et al. 2005

Diabetes

126

View full text Add to dashboard Cite

The recent success in restoring normoglycemia in type 1 diabetes by islet cell transplantation indicates that cell replacement therapy of this severe disease is achievable. However, the severe lack of donor islets has increased the demand for alternative sources of ␤-cells, such as adult and embryonic stem cells. Here, we investigate the potential of human embryonic stem cells (hESCs) to differentiate into ␤-cells. T he pancreatic islets of Langerhans originate from definitive endoderm. The path from definitive endoderm to the mature hormone-producing islet cell types is complex and involves sequential cell-fate decisions, including formation of pancreatic endoderm, endocrine progenitors, and hormone-producing islet cell types, including ␤-cells. Systematic studies of the developmental biology of the pancreas have generated important knowledge about the lineage relationship between the different pancreatic cell types and the transcriptional machinery that regulates cell-type specification (1-3). In addition, important information about the extracellular signals that orchestrate pancreatic cell differentiation and morphogenesis has recently emerged (2,4). However, much remains to be learned about the extracellular cues that specify, maintain, expand, and differentiate endocrine progenitors. Taking these facts into account, the objective to in vitro control differentiation of undifferentiated embryonic stem cells into bona fide pancreatic ␤-cells via the sequential cell-fate decisions that operate during normal ␤-cell development will be a challenging task.The potential use of human embryonic stem cells (hESCs) as a source for new ␤-cells in cell replacement therapy of type 1 diabetes and as a tool to study human ␤-cell development has created great interest in devising strategies for coaxing hESCs into pancreatic ␤-cells. The rationale for the former is that cell replacement therapy of this severe disease already exists in the form of islet transplantation, but cadaveric islets available from donors are insufficient for the present and future need in islet transplantation. Thus, the unique nature of hESCs to either self-renew or differentiate into most of our cell types, presumably also islet cell types, including ␤-cells, suggests that these cells could potentially supply an unlimited source of transplantable islet cells in the future.Recent studies have shown that insulin ϩ cells can be generated from embryonic stem cells by the use of different experimental strategies (5-14). For example, spontaneous differentiation of mouse embryonic stem cells resulted in ineffective differentiation of insulin-producing cells (8). The most frequently used approach is based on the findings that similar mechanisms operate to control the development of both the central nervous system and the pancreas (15-17) and that insulin-producing cells have been observed in the nervous system of invertebrates (18 -20) and in primary cell cultures from mammalian fetal brain (21). Specifically, embryonic stem cells were induced to different...

show abstract

“…Test results that come the closest to measuring the function of islets are only available after a clinical islet transplant is completed. These tests include the glucosestimulated insulin secretion assay (Ashcroft et al 1971, Andersson et al 1976, Gray et al 1984, de Haan et al 2004) and the transplantation of human islets into diabetic and non-diabetic animal models (Lake et al 1988, Gaber et al 2004.…”

Section: Introductionmentioning

confidence: 99%

Increased oxygen consumption rates in response to high glucose detected by a novel oxygen biosensor system in non-human primate and human islets

Wang¹,

Upshaw²,

Strong³

et al. 2005

Journal of Endocrinology

View full text Add to dashboard Cite

In this study, we investigated the use of a novel oxygen biosensor system to detect changes in oxygen consumption rates (OCRs) by islets in response to glucose. Islets from non-human primate and human pancreata were seeded into an oxygen biosensor system microplate and exposed to basal (2·8 or 5·6 mM) or high (16·7 or 33·3 mM) glucose over either a long-term or a short-term culture. Our data clearly demonstrated that non-human primate islets cultured in high glucose conditions exhibited significant increases in OCRs over a 168 h extended culture period (P<0·05), which indicates an accelerated rate of -cell metabolism triggered by glucose over time. Significant increases in OCRs (P<0·01) were also attained in both non-human primate and human islets exposed to high glucose conditions in a 120 min short-term incubation period. OCRs exhibited by human islets exposed to different glucose concentrations correlated with insulin secretion (r 2 =0·7681, P<0·01). Moreover, the OCR stimulation index (i.e. OCR at high glucose/OCR at basal glucose) was significantly greater in human islets displaying high viabilities as opposed to islets exhibiting low viabilities (P<0·05). Together these data demonstrate that this novel oxygen biosensor system documents significant increases in islet oxygen consumption upon acute and chronic exposure to high glucose concentrations. Importantly, this methodology rapidly and robustly detects changes in OCRs by islets in response to high glucose stimulation that correlate well with the metabolic activities and functional viability of islets and clearly delineates significant differences in OCR stimulation index between high and low viability human islets, and therefore may prove to be an effective approach for quickly assessing the functional viability of islets prior to transplantation.

show abstract

Human islet graft function in NOD-SCID mice predicts clinical response in islet transplant recipients

Cited by 30 publications

References 6 publications

Glucose Stimulation of Cytochrome C Reduction and Oxygen Consumption as Assessment of Human Islet Quality

Glucose Stimulation of Cytochrome C Reduction and Oxygen Consumption as Assessment of Human Islet Quality

Signals From the Embryonic Mouse Pancreas Induce Differentiation of Human Embryonic Stem Cells Into Insulin-Producing β-Cell–Like Cells

Increased oxygen consumption rates in response to high glucose detected by a novel oxygen biosensor system in non-human primate and human islets

Contact Info

Product

Resources

About