Re-engineering islet cell transplantation

Fotino, Nicoletta; Fotino, Carmen; Pileggi, Antonello

doi:10.1016/j.phrs.2015.02.010

Cited by 38 publications

(20 citation statements)

References 146 publications

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“…The final objective of developing an extrahepatic site for islet transplantation is not only the ability to provide physiologic portal drainage of endocrine pancreas secretions but also the possibility of engineering the transplant microenvironment for the development of successful biologic replacement strategies that could avoid the need for chronic recipient immunosuppression (14,15). Ideal characteristics of such a site include sufficient space to accommodate relatively large tissue volumes (e.g., low-purity or encapsulated insulin-producing cell products), allow for minimally invasive transplant procedures, and enable noninvasive longitudinal monitoring and access for graft biopsy and/or retrieval, as well as physiologic venous drainage through the portal system (14,15).…”

Section: Introductionmentioning

confidence: 99%

Bioengineering the Endocrine Pancreas: Intraomental Islet Transplantation Within a Biologic Resorbable Scaffold

Berman¹,

et al. 2016

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Transplantation of pancreatic islets is a therapeutic option to preserve or restore β-cell function. Our study was aimed at developing a clinically applicable protocol for extrahepatic transplantation of pancreatic islets. The potency of islets implanted onto the omentum, using an in situ–generated adherent, resorbable plasma-thrombin biologic scaffold, was evaluated in diabetic rat and nonhuman primate (NHP) models. Intraomental islet engraftment in the biologic scaffold was confirmed by achievement of improved metabolic function and preservation of islet cytoarchitecture, with reconstitution of rich intrainsular vascular networks in both species. Long-term nonfasting normoglycemia and adequate glucose clearance (tolerance tests) were achieved in both intrahepatic and intraomental sites in rats. Intraomental graft recipients displayed lower levels of serum biomarkers of islet distress (e.g., acute serum insulin) and inflammation (e.g., leptin and α2-macroglobulin). Importantly, low-purity (30:70% endocrine:exocrine) syngeneic rat islet preparations displayed function equivalent to that of pure (>95% endocrine) preparations after intraomental biologic scaffold implantation. Moreover, the biologic scaffold sustained allogeneic islet engraftment in immunosuppressed recipients. Collectively, our feasibility/efficacy data, along with the simplicity of the procedure and the safety of the biologic scaffold components, represented sufficient preclinical testing to proceed to a pilot phase I/II clinical trial.

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Section: Introductionmentioning

confidence: 99%

Bioengineering the Endocrine Pancreas: Intraomental Islet Transplantation Within a Biologic Resorbable Scaffold

Berman¹,

et al. 2016

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“…Numerous studies have reported efforts to improve the survival of islets by preventing the loss of islet cell viability and function during and following transplantation. Strategies to robustly condition pancreatic islets, which include promotion of cell growth and metabolic functions, are particularly important (5)(6)(7).…”

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confidence: 99%

Beneficial effects of growth hormone-releasing hormone agonists on rat INS-1 cells and on streptozotocin-induced NOD/SCID mice

Zhang

Cui

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Agonists of growth hormone-releasing hormone (GHRH) have been previously reported to promote growth, function, and engraftment of islet cells following transplantation. Here we evaluated recently synthesized GHRH agonists on the proliferation and biological functions of rat pancreatic β-cell line (INS-1) and islets. In vitro treatment of INS-1 cells with GHRH agonists increased cell proliferation, the expression of cellular insulin, insulin-like growth factor-1 (IGF1), and GHRH receptor, and also stimulated insulin secretion in response to glucose challenge. Exposure of INS-1 cells to GHRH agonists, MR-356 and MR-409, induced activation of ERK and AKT pathways. Agonist MR-409 also significantly increased the levels of cellular cAMP and the phosphorylation of cAMP response element binding protein (CREB) in INS-1 cells. Treatment of rat islets with agonist, MR-409 significantly increased cell proliferation, islet size, and the expression of insulin. In vivo daily s.c. administration of 10 μg MR-409 for 3 wk dramatically reduced the severity of streptozotocin (STZ)-induced diabetes in nonobese diabetic severe combined immunodeficiency (NOD/SCID) mice. The maximal therapeutic benefits with respect to the efficiency of engraftment, ability to reach normoglycemia, gain in body weight, response to high glucose challenge, and induction of higher levels of serum insulin and IGF1 were observed when diabetic mice were transplanted with rat islets preconditioned with GHRH agonist, MR-409, and received additional treatment with MR-409 posttransplantation. This study provides an improved approach to the therapeutic use of GHRH agonists in the treatment of diabetes mellitus.GHRH agonists | diabetes | INS-1 | signaling pathways | transplantation

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“…If such an approach could potentially be tailored to reverse the tumorigenic status of 1.1B4 cells, the therapeutic qualities observed in this study could be more usefully exploited for the treatment of T1DM. An additional or alternative approach involves the use of implantation devices that are currently under development[7,52]. These devices, such as TheraCyte™ macroencapsulation system and nanofiber-enabled encapsulation devices support cell function by providing good oxygen tension and protection from autoimmune attack, whilst providing against unwanted growth and spread of implanted cells[7,52,53].…”

Section: Discussionmentioning

confidence: 99%

“…Hypoglycaemic episodes are not uncommon especially in brittle diabetes where patients often exhibit hypoglycaemia unawareness resulting in dangerous iatrogenic hypoglycaemia[6]. Cellular delivery of insulin achieved by replacement of pancreatic β-cells can help manage diabetes and in some cases eliminate the need for exogenous insulin therapy[7]. …”

Section: Introductionmentioning

confidence: 99%

Implanting 1.1B4 human β-cell pseudoislets improves glycaemic control in diabetic severe combined immune deficient mice

Green¹,

Vasu²,

McClenaghan³

et al. 2016

WJD

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AIMTo investigate the potential of implanting pseudoislets formed from human insulin-releasing β-cell lines as an alternative to islet transplantation.METHODSIn this study, the anti-diabetic potential of novel human insulin releasing 1.1B4 β-cells was evaluated by implanting the cells, either as free cell suspensions, or as three-dimensional pseudoislets, into the subscapular region of severe combined immune deficient mice rendered diabetic by single high-dose administration of streptozotocin. Metabolic parameters including food and fluid intake, bodyweight and blood glucose were monitored throughout the study. At the end of the study animals were given an intraperitoneal glucose tolerance test. Animals were then culled and blood and tissues were collected for analysis. Insulin and glucagon contents of plasma and tissues were measured by insulin radioimmunoassay and chemiluminescent enzyme-linked immunosorbance assay respectively. Histological analyses of pancreatic islets were carried out by quantitative fluorescence immunohistochemistry staining.RESULTSBoth pseudoislet and cell suspension implants yielded well vascularised β-cell masses of similar insulin content. This was associated with progressive amelioration of hyperphagia (P < 0.05), polydipsia (P < 0.05), body weight loss (P < 0.05), hypoinsulinaemia (P < 0.05), hyperglycaemia (P < 0.05 - P < 0.001) and glucose tolerance (P < 0.01). Islet morphology was also significantly improved in both groups of transplanted mice, with increased β-cell (P < 0.05 - P < 0.001) and decreased alpha cell (P < 0.05 - P < 0.001) areas. Whereas mice receiving 1.1B4 cell suspensions eventually exhibited hypoglycaemic complications, pseudoislet recipients displayed a more gradual amelioration of diabetes, and achieved stable blood glucose control similar to non-diabetic mice at the end of the study.CONCLUSIONAlthough further work is needed to address safety issues, these results provide proof of concept for possible therapeutic applicability of human β-cell line pseudoislets in diabetes.

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Re-engineering islet cell transplantation

Cited by 38 publications

References 146 publications

Bioengineering the Endocrine Pancreas: Intraomental Islet Transplantation Within a Biologic Resorbable Scaffold

Bioengineering the Endocrine Pancreas: Intraomental Islet Transplantation Within a Biologic Resorbable Scaffold

Beneficial effects of growth hormone-releasing hormone agonists on rat INS-1 cells and on streptozotocin-induced NOD/SCID mice

Implanting 1.1B4 human β-cell pseudoislets improves glycaemic control in diabetic severe combined immune deficient mice

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