Islet-like organoids derived from human pluripotent stem cells efficiently function in the glucose responsiveness in vitro and in vivo

• Published in: Scientific reports Vol. 6; no. 1; p. 35145
• Main Authors: Kim, Youngjin, Kim, Hyeongseok, Ko, Ung Hyun, Oh, Youjin, Lim, Ajin, Sohn, Jong-Woo, Shin, Jennifer H., Kim, Hail, Han, Yong-Mahn
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.10.2016; Nature Publishing Group
• Subjects: 13/100; 13/31; 14/19; 14/28; 14/63; 38/1; 38/77; 631/136/532; 631/532/1360; 631/532/2064; 64/60; Animals; Blood glucose; Blood Glucose - metabolism; Cell Aggregation; Cell Differentiation; Cells, Cultured; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - blood; Diabetes Mellitus, Experimental - therapy; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; Glucose; Glucose - metabolism; Hormones; Humanities and Social Sciences; Humans; In Vitro Techniques; Insulin; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - metabolism; Islets of Langerhans; Islets of Langerhans - cytology; Islets of Langerhans - metabolism; Islets of Langerhans Transplantation; Mice; Mice, Inbred NOD; Mice, SCID; multidisciplinary; Organoids; Organoids - cytology; Organoids - metabolism; Pancreas transplantation; Pancreatic islet transplantation; Pluripotency; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - metabolism; Rodents; Science; Secretion; Somatostatin; Stem cell transplantation; Stem cells
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep35145

Insulin secretion is elaborately modulated in pancreatic ß cells within islets of three-dimensional (3D) structures. Using human pluripotent stem cells (hPSCs) to develop islet-like structures with insulin-producing ß cells for the treatment of diabetes is challenging. Here, we report that pancreatic islet-like clusters derived from hESCs are functionally capable of glucose-responsive insulin secretion as well as therapeutic effects. Pancreatic hormone-expressing endocrine cells (ECs) were differentiated from hESCs using a step-wise protocol. The hESC-derived ECs expressed pancreatic endocrine hormones, such as insulin, somatostatin, and pancreatic polypeptide. Notably, dissociated ECs autonomously aggregated to form islet-like, 3D structures of consistent sizes (100–150 μm in diameter). These EC clusters (ECCs) enhanced insulin secretion in response to glucose stimulus and potassium channel inhibition in vitro . Furthermore, ß cell-deficient mice transplanted with ECCs survived for more than 40 d while retaining a normal blood glucose level to some extent. The expression of pancreatic endocrine hormones was observed in tissues transplanted with ECCs. In addition, ECCs could be generated from human induced pluripotent stem cells. These results suggest that hPSC-derived, islet-like clusters may be alternative therapeutic cell sources for treating diabetes.