A Cell-Based Approach for Diabetes Treatment Using Engineered Non-β Cells

Bara, Heather; Thulé, Peter M.; Sambanis, Athanassios

doi:10.1177/193229680900300321

Cited by 5 publications

(7 citation statements)

References 29 publications

(1 reference statement)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The average human insulin serum concentration in treated mice was 9-fold higher than that reported in diabetic mice treated with GLUTag-INS macrocapsule constructs, and similar to murine insulin concentrations in healthy mice (12). Blood insulin concentration profiles were generated to determine whether serum insulin measurements were reasonable (Figure 5).…”

Section: Discussionsupporting

confidence: 63%

“…However, Unniappan et al found that microencapsulated insulin-producing K-cells were unable to control blood sugars until a drug-inducible element was incorporated into the insulin transgene (9). Alternatively, Bara et al seeded human insulin-secreting L-cells in a macrocapsule device for transplantation (10–12), but blood glucose levels were unaffected. Insufficient insulin secretion and limitations imposed by macrocapsules were two likely barriers that prevented these systems from serving as standalone diabetes treatments.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Therapeutic Effects of a Non–β Cell Bioartificial Pancreas in Diabetic Mice

Tiernan

Thulé²,

Sambanis³

2014

Transplantation

Self Cite

View full text Add to dashboard Cite

Background Cell-based insulin therapies can potentially improve glycemic regulation in insulin dependent diabetes patients. Enteroendocrine cells engineered to secrete recombinant insulin have exhibited glycemic efficacy, but have been primarily studied as uncontrollable growth systems in immune incompetent mice. Furthermore, reports suggest that suboptimal insulin secretion remains a barrier to expanded application. Methods Genetic and tissue engineering strategies were applied to improve recombinant insulin secretion from intestinal L-cells on both a per-cell and per-graft basis. Transduction of insulin-expressing GLUTag L-cells with lentivirus carrying an additional human insulin gene enhanced secretion 2-fold. We infected cells with lentivirus expressing a luciferase reporter gene to track cell survival in vivo. To provide a growth-controlled and immune protective environment without affecting secretory capacity, cells were microencapsulated in barium alginate. Approximately 9×107 microencapsulated cells were injected intraperitoneally in immune competent streptozotocin-induced diabetic mice for therapeutic efficacy evaluation. Results Graft insulin secretion was increased to 16–24 mU insulin/day. Transient normoglycemia was achieved in treated mice two days after transplantation, and endogenous insulin was sufficient to sustain body weights of treated mice receiving minimal supplementation. Conclusions Glycemic efficacy of a bioartificial pancreas based on insulin-secreting enteroendocrine cells is insufficient as a standalone therapy, despite enhancement of graft insulin secretion capacity. Supplemental strategies to alleviate secretion limitations should be pursued.

show abstract

Section: Discussionsupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Therapeutic Effects of a Non–β Cell Bioartificial Pancreas in Diabetic Mice

Tiernan

Thulé²,

Sambanis³

2014

Transplantation

Self Cite

View full text Add to dashboard Cite

show abstract

“…Haematoxylin/eosin (H&E) histological images of microcapsules were obtained as previously described (Goh et al ., ), with resin embedding. Insulin secretion was measured as previously described (Bara et al ., ), with insulin assayed using insulin radioimmunoassay (Millipore, Billerica, MA). Briefly, insulin secretion tests were performed on 0.1 ml volumes of microcapsules in 100 µm strainers placed in 12‐well plates containing 5 ml basal or stimulating medium.…”

Section: Methodsmentioning

confidence: 99%

Bioluminescence tracking of alginate micro-encapsulated cell transplants

Tiernan

Sambanis

2014

J Tissue Eng Regen Med

Self Cite

View full text Add to dashboard Cite

Cell-based therapies to treat loss-of-function hormonal disorders such as diabetes and Parkinson's disease are routinely coupled with encapsulation strategies, but an understanding of when and why grafts fail in vivo is lacking. Consequently, investigators cannot clearly define the key factors that influence graft success. Although bioluminescence is a popular method to track the survival of free cells transplanted in preclinical models, little is known of the ability to use bioluminescence for real-time tracking of microencapsulated cells. Furthermore, the impact that dynamic imaging distances may have, due to freely-floating microcapsules in vivo, on cell survival monitoring is unknown. This work addresses these questions by applying bioluminescence to a pancreatic substitute based on microencapsulated cells. Recombinant insulin-secreting cells were transduced with a luciferase lentivirus and microencapsulated in Ba crosslinked alginate for in vitro and in vivo studies. In vitro quantitative bioluminescence monitoring was possible and viable microencapsulated cells were followed in real time under both normoxic and anoxic conditions. Although in vivo dispersion of freely-floating microcapsules in the peritoneal cavity limited the analysis to a qualitative bioluminescence evaluation, signals consistently four orders of magnitude above background were clear indicators of temporal cell survival. Strong agreement between in vivo and in vitro cell proliferation over time was discovered by making direct bioluminescence comparisons between explanted microcapsules and parallel in vitro cultures. Broader application of this bioluminescence approach to retrievable transplants, in supplement to currently used end-point physiological tests, could improve understanding and accelerate development of cell-based therapies for critical clinical applications. Copyright © 2014 John Wiley & Sons, Ltd.

show abstract

“…Murine glucagon gene‐simian virus‐40 large T‐antigen cells transfected with a plasmid containing the human insulin gene driven by a cytomegalovirus promoter were capable of secreting both GLP‐1 and mature insulin in response to multiple secretagogues; however, the transfected cells did not increase insulin secretion when stimulated with different concentrations of glucose. Furthermore, transplanted engineered glucagon gene‐simian virus‐40 large T‐antigen cells did not produce enough insulin to ameliorate diabetes in mice. Murine STC‐1 cells, which produce a number of gut hormones including GLP‐1, were transfected with a plasmid containing the insulin gene driven by a proglucagon promoter.…”

Section: Targeting Gut Enteroendocrine Cellsmentioning

confidence: 99%

Engineering the gut for insulin replacement to treat diabetes

Mahdavi

Glavas

Kieffer

2016

J of Diabetes Invest

View full text Add to dashboard Cite

The gut epithelium's large surface area, its direct exposure to ingested nutrients, its vast stem cell population and its immunotolerogenic environment make it an excellent candidate for therapeutic cells to treat diabetes. Thus, several attempts have been made to coax immature gut cells to differentiate into insulin‐producing cells by altering the expression patterns of specific transcription factors. Furthermore, because of similarities in enteroendocrine and pancreatic endocrine cell differentiation pathways, other approaches have used genetically engineered enteroendocrine cells to produce insulin in addition to their endogenous secreted hormones. Several studies support the utility of both of these approaches for the treatment of diabetes. Converting a patient's own gut cells into meal‐regulated insulin factories in a safe and immunotolerogenic environment is an attractive approach to treat and potentially cure diabetes. Here, we review work on these approaches and indicate where we feel further advancements are required.

show abstract

A Cell-Based Approach for Diabetes Treatment Using Engineered Non-β Cells

Abstract: A variety of cell types and of encapsulation methods to enhance immune acceptance of insulin-secreting grafts are being pursued. Recombinant enteroendocrine cells show promise, but it is likely that they need to be combined with recombinant hepatic cells to achieve glycemic normalization.

Cited by 5 publications

References 29 publications

Therapeutic Effects of a Non–β Cell Bioartificial Pancreas in Diabetic Mice

Therapeutic Effects of a Non–β Cell Bioartificial Pancreas in Diabetic Mice

Bioluminescence tracking of alginate micro-encapsulated cell transplants

Engineering the gut for insulin replacement to treat diabetes

Contact Info

Product

Resources

About