Differentiation of Microencapsulated Neonatal Porcine Pancreatic Cell Clusters in Vitro Improves Transplant Efficacy in Type 1 Diabetes Mellitus Mice

Author:

Cheon Gyeong-JinORCID,Park Heon-Seok,Lee Eun-Young,Kim Min Jung,You Young-Hye,Rhee Marie,Kim Ji-Won,Yoon Kun-HoORCID

Abstract

Background: Neonatal porcine pancreatic cell clusters (NPCCs) have been proposed as an alternative source of β cells for islet transplantation because of their low cost and growth potential after transplantation. However, the delayed glucose lowering effect due to the immaturity of NPCCs and immunologic rejection remain as a barrier to NPCC’s clinical application. Here, we demonstrate accelerated differentiation and immune-tolerant NPCCs by <i>in vitro</i> chemical treatment and microencapsulation.Methods: NPCCs isolated from 3-day-old piglets were cultured in F-10 media and then microencapsulated with alginate on day 5. Differentiation of NPCCs is facilitated by media supplemented with activin receptor-like kinase 5 inhibitor II, triiodothyronine and exendin-4 for 2 weeks. Marginal number of microencapsulated NPCCs to cure diabetes with and without differentiation were transplanted into diabetic mice and observed for 8 weeks.Results: The proportion of insulin-positive cells and insulin mRNA levels of NPCCs were significantly increased <i>in vitro</i> in the differentiated group compared with the undifferentiated group. Blood glucose levels decreased eventually after transplantation of microencapsulated NPCCs in diabetic mice and normalized after 7 weeks in the differentiated group. In addition, the differentiated group showed nearly normal glucose tolerance at 8 weeks after transplantation. In contrast, neither blood glucose levels nor glucose tolerance were improved in the undifferentiated group. Retrieved graft in the differentiated group showed greater insulin response to high glucose compared with the undifferentiated group.Conclusion: <i>in vitro</i> differentiation of microencapsulated immature NPCCs increased the proportion of insulin-positive cells and improved transplant efficacy in diabetic mice without immune rejection.

Funder

National Research Foundation of Korea

Ministry of Education

Rural Development Administration

Publisher

Korean Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism

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