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Hirshberg, Boaz; Rother, Kristina I.; Digon, Benigno J.; Venstrom, Jeffrey M.; Harlan, David M.

doi:10.1023/a:1027358230402

Cited by 23 publications

(7 citation statements)

References 75 publications

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“…Daily administration of exogenous insulin is still the mainstay of treatment, but this is not always sufficient to prevent chronic complications of the retina, kidneys, peripheral nerves, and blood vessels. Replacement of β cells (either by whole pancreas or islet cell transplantation) is the best available method for restoring a physiologic glycemic control and improvement of diabetes complications [ 3 , 4 ]. As with other types of organ transplantation, shortcomings related to islet or whole pancreas transplantation include the high medical and surgical costs, insufficient supply of available donor pancreata, and lifetime requirement for immunosuppression therapy—that is variably associated with adverse side-effects [ 3 , 5 – 7 ].…”

Section: Introductionmentioning

confidence: 99%

Reprogramming human gallbladder cells into insulin-producing β-like cells

et al. 2017

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The gallbladder and cystic duct (GBCs) are parts of the extrahepatic biliary tree and share a common developmental origin with the ventral pancreas. Here, we report on the very first genetic reprogramming of patient-derived human GBCs to β-like cells for potential autologous cell replacement therapy for type 1 diabetes. We developed a robust method for large-scale expansion of human GBCs ex vivo. GBCs were reprogrammed into insulin-producing pancreatic β-like cells by a combined adenoviral-mediated expression of hallmark pancreatic endocrine transcription factors PDX1, MAFA, NEUROG3, and PAX6 and differentiation culture in vitro. The reprogrammed GBCs (rGBCs) strongly induced the production of insulin and pancreatic endocrine genes and these responded to glucose stimulation in vitro. rGBCs also expressed an islet-specific surface marker, which was used to enrich for the most highly reprogrammed cells. More importantly, global mRNA and microRNA expression profiles and protein immunostaining indicated that rGBCs adopted an overall β-like state and these rGBCs engrafted in immunodeficient mice. Furthermore, comparative global expression analyses identified putative regulators of human biliary to β cell fate conversion. In summary, we have developed, for the first time, a reliable and robust genetic reprogramming and culture expansion of primary human GBCs—derived from multiple unrelated donors—into pancreatic β-like cells ex vivo, thus showing that human gallbladder is a potentially rich source of reprogrammable cells for autologous cell therapy in diabetes.

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Section: Introductionmentioning

confidence: 99%

Reprogramming human gallbladder cells into insulin-producing β-like cells

et al. 2017

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“…The freedom from daily insulin injections and blood glucose monitoring is reported to improve the successfully transplanted recipient's sense of well being, independence, and promote a perception of normality [17]. …”

Section: Human Islet Transplantationmentioning

confidence: 99%

“…In addition, even the most up-to-date islet isolation facility achieves an isolated islet yield of sufficient quality and quantity to transplant only every second isolation [30]. Taking also into account that almost all islet recipients currently require islets from 2–4 donors, then only less than 1000 recipients per year (out of the 17 million in need) could benefit from an islet transplantation [17]. …”

Section: Human Islet Transplantationmentioning

confidence: 99%

“…In a primate model it was shown that islet de novo capillary formation seems to be established between 5 and 30 days after transplantation. Before this time period, islets have to cope not only with a reduced pO 2 but possibly also with changes associated with the basement membrane components of the endothelial cells which are known signals promoting β-cell function [17]. Future studies will show whether the addition of matrix components may partially substitute for endothelial cells and thereby bridge the time until new capillaries and vascular basement membranes are formed in the transplanted islets.…”

Section: Revascularization Of Transplanted Isletsmentioning

confidence: 99%

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Molecular and cellular key players in human islet transplantation

Hermann

Margreiter

Hengster

2007

J Cellular Molecular Medi

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Human islet transplantation could represent an attractive alternative to insulin injections for the treatment of diabetes type 1. However, such an approach requires a better understanding of the molecular and cellular switches controlling β-cell function in general as well as after transplantation into the liver. Although much research has been done into the suitability of stem or progenitor cells to generate a limitless supply of human β-cells, a reproducible and efficient protocol for the differentiation of such cells into stably insulin-secreting β-cells suitable for transplantation has yet to be reported. Fueled by recent findings showing that mature β-cells are able to regenerate, many efforts have been undertaken to expand this cell pool. Unfortunately, also these approaches had problems to yield sufficiently differentiated human islet cells. The aim of this review is to summarize recent findings describing some of the molecular and cellular key players of islet biology. A more complete understanding of their orchestration and the use of new methods such as real time confocal imaging for the assessment of islet quality may yield the necessary advancements for more successful human islet transplantation.

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“…However, such facilities involve the necessity to ship islets from the isolation to the transplantation facility, thereby negatively influencing islet cell quality. Despite its importance there is no consensus on a clinically feasible solution for the transport of islets [6–9]. …”

Section: Introductionmentioning

confidence: 99%

Rotational Transport of Islets: The Best Way for Islets to Get around?

Oberhuber

Mittermair²,

Zelger

et al. 2013

BioMed Research International

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Islet transplantation is a valid treatment option for patients suffering from type 1 diabetes mellitus. To assure optimal islet cell quality, specialized islet isolation facilities have been developed. Utilization of such facilities necessitates transportation of islet cells to distant institutions for transplantation. Despite its importance, a clinically feasible solution for the transport of islets has still not been established. We here compare the functionality of isolated islets from C57BL/6 mice directly after the isolation procedure as well as after two simulated transport conditions, static versus rotation. Islet cell quality was assessed using real-time live confocal microscopy. In vivo islet function after syngeneic transplantation was determined by weight and blood sugar measurements as well as by intraperitoneal glucose tolerance tests. Vascularization of islets was documented by fluorescence microscopy and immunohistochemistry. All viability parameters documented comparable cell viability in the rotary group and the group transplanted immediately after isolation. Functional parameters assessed in vivo displayed no significant difference between these two groups. Moreover, vascularization of islets was similar in both groups. In conclusion, rotary culture conditions allows the maintenance of highest islet quality for at least 15 h, which is comparable to that of freshly isolated islets.

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Cited by 23 publications

References 75 publications

Reprogramming human gallbladder cells into insulin-producing β-like cells

Reprogramming human gallbladder cells into insulin-producing β-like cells

Molecular and cellular key players in human islet transplantation

Rotational Transport of Islets: The Best Way for Islets to Get around?

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