Dataset Information

?-Cell Replacement in Mice Using Human Type 1 Diabetes Nuclear Transfer Embryonic Stem Cells.

ABSTRACT: ?-Cells derived from stem cells hold great promise for cell replacement therapy for diabetes. Here we examine the ability of nuclear transfer embryonic stem cells (NT-ESs) derived from a patient with type 1 diabetes to differentiate into ?-cells and provide a source of autologous islets for cell replacement. NT-ESs differentiate in vitro with an average efficiency of 55% into C-peptide-positive cells, expressing markers of mature ?-cells, including MAFA and NKX6.1. Upon transplantation in immunodeficient mice, grafted cells form vascularized islet-like structures containing MAFA/C-peptide-positive cells. These ?-cells adapt insulin secretion to ambient metabolite status and show normal insulin processing. Importantly, NT-ES-?-cells maintain normal blood glucose levels after ablation of the mouse endogenous ?-cells. Cystic structures, but no teratomas, were observed in NT-ES-?-cell grafts. Isogenic induced pluripotent stem cell lines showed greater variability in ?-cell differentiation. Even though different methods of somatic cell reprogramming result in stem cell lines that are molecularly indistinguishable, full differentiation competence is more common in ES cell lines than in induced pluripotent stem cell lines. These results demonstrate the suitability of NT-ES-?-cells for cell replacement for type 1 diabetes and provide proof of principle for therapeutic cloning combined with cell therapy.

SUBMITTER: Sui L

PROVIDER: S-EPMC5741143 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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β-Cell Replacement in Mice Using Human Type 1 Diabetes Nuclear Transfer Embryonic Stem Cells.

Sui Lina L Danzl Nichole N Campbell Sean R SR Viola Ryan R Williams Damian D Xing Yuan Y Wang Yong Y Phillips Neil N Poffenberger Greg G Johannesson Bjarki B Oberholzer Jose J Powers Alvin C AC Leibel Rudolph L RL Chen Xiaojuan X Sykes Megan M Egli Dieter D

Diabetes 20170920 1

β-Cells derived from stem cells hold great promise for cell replacement therapy for diabetes. Here we examine the ability of nuclear transfer embryonic stem cells (NT-ESs) derived from a patient with type 1 diabetes to differentiate into β-cells and provide a source of autologous islets for cell replacement. NT-ESs differentiate in vitro with an average efficiency of 55% into C-peptide-positive cells, expressing markers of mature β-cells, including MAFA and NKX6.1. Upon transplantation in immuno ...[more]

PMID: 28931519

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Project description:: A depleted ?-cell mass causes diabetes complications that cannot be avoided by insulin administration. ?-Cell replacement can stop their development when restoring insulin's homeostatic role. This requires a sufficient number and an adequate functional state of the ? cells, together defined as "functional ?-cell mass." Intraportal implants of human pancreatic islet cells correct hyperglycemia in patients with type 1 diabetes, but this effect is transient and often incomplete. Studies to improve outcome are hindered by shortage in donor pancreases. Human pluripotent stem cells are a candidate source for mass production of grafts for ?-cell replacement. Their in vitro differentiation to pancreatic endoderm (stage 4) and to ?-cell-containing preparations (stage 7) provides grafts that generate ?-cell implants in mice. In vivo markers indicated a better outcome of device-encapsulated stage 4 cells and microencapsulated stage 7 cells as compared with nonencapsulated grafts. Encapsulation also offers the advantage of representative implant retrieval for direct analysis by ex vivo markers. Combination of in vitro, in vivo, and ex vivo markers allows comparison of different stem cell-derived grafts and implants, with each other and with clinical islet cell preparations that serve as reference. Data in mice provide insights into the biology of stem cell-generated ?-cell implants, in particular their capacity to establish and sustain a functional ?-cell mass. They can thus be indicative for translation of a graft to similar studies in patients, where metabolic benefit will be an additional marker of primordial importance.Human stem cell-derived preparations can generate insulin-producing implants in immune-incompetent mice. Steps are undertaken for translation to patients with type 1 diabetes. Their therapeutic significance will depend on their capacity to establish a functional ?-cell mass that provides metabolic benefit. This study proposes the combined use of in vitro, in vivo, and ex vivo markers to assess this potential in preclinical models and in clinical studies.

Dataset Information

?-Cell Replacement in Mice Using Human Type 1 Diabetes Nuclear Transfer Embryonic Stem Cells.

Publications

β-Cell Replacement in Mice Using Human Type 1 Diabetes Nuclear Transfer Embryonic Stem Cells.

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