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Conformal Coating of Stem Cell-Derived Islets for ? Cell Replacement in Type 1 Diabetes.

ABSTRACT: The scarcity of donors and need for immunosuppression limit pancreatic islet transplantation to a few patients with labile type 1 diabetes. Transplantation of encapsulated stem cell-derived islets (SC islets) might extend the applicability of islet transplantation to a larger cohort of patients. Transplantation of conformal-coated islets into a confined well-vascularized site allows long-term diabetes reversal in fully MHC-mismatched diabetic mice without immunosuppression. Here, we demonstrated that human SC islets reaggregated from cryopreserved cells display glucose-stimulated insulin secretion in vitro. Importantly, we showed that conformally coated SC islets displayed comparable in vitro function with unencapsulated SC islets, with conformal coating permitting physiological insulin secretion. Transplantation of SC islets into the gonadal fat pad of diabetic NOD-scid mice revealed that both unencapsulated and conformal-coated SC islets could reverse diabetes and maintain human-level euglycemia for more than 80 days. Overall, these results provide support for further evaluation of safety and efficacy of conformal-coated SC islets in larger species.

SUBMITTER: Stock AA

PROVIDER: S-EPMC6962554 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Conformal Coating of Stem Cell-Derived Islets for β Cell Replacement in Type 1 Diabetes.

Stock Aaron A AA Manzoli Vita V De Toni Teresa T Abreu Maria M MM Poh Yeh-Chuin YC Ye Lillian L Roose Adam A Pagliuca Felicia W FW Thanos Chris C Ricordi Camillo C Tomei Alice A AA

Stem cell reports 20191212 1

The scarcity of donors and need for immunosuppression limit pancreatic islet transplantation to a few patients with labile type 1 diabetes. Transplantation of encapsulated stem cell-derived islets (SC islets) might extend the applicability of islet transplantation to a larger cohort of patients. Transplantation of conformal-coated islets into a confined well-vascularized site allows long-term diabetes reversal in fully MHC-mismatched diabetic mice without immunosuppression. Here, we demonstrated ...[more]

PMID: 31839542

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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

Conformal Coating of Stem Cell-Derived Islets for ? Cell Replacement in Type 1 Diabetes.

Publications

Conformal Coating of Stem Cell-Derived Islets for β Cell Replacement in Type 1 Diabetes.

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