title: Islet-like organoids derived from human pluripotent stem cells efficiently function in the glucose responsiveness in vitro and in vivo.
abstract: 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.
authors.affiliation: Department of Biological Sciences, KAIST, Daejeon 34141, Republic of Korea.
authors.forename: Youngjin
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea.
authors.forename: Hyeongseok
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Mechanical Engineering, KAIST, Daejeon, 34141, Republic of Korea.
authors.forename: Ung Hyun
authors.initials: UH
authors.lastname: Ko
authors.affiliation: Department of Biological Sciences, KAIST, Daejeon 34141, Republic of Korea.
authors.forename: Youjin
authors.initials: Y
authors.lastname: Oh
authors.affiliation: Department of Biological Sciences, KAIST, Daejeon 34141, Republic of Korea.
authors.forename: Ajin
authors.initials: A
authors.lastname: Lim
authors.affiliation: Department of Biological Sciences, KAIST, Daejeon 34141, Republic of Korea.
authors.forename: Jong-Woo
authors.initials: JW
authors.lastname: Sohn
authors.affiliation: Department of Mechanical Engineering, KAIST, Daejeon, 34141, Republic of Korea.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Shin
authors.affiliation: Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea.
authors.forename: Hail
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, KAIST, Daejeon 34141, Republic of Korea.
authors.forename: Yong-Mahn
authors.initials: YM
authors.lastname: Han
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002449:Cell Aggregation; D002454:Cell Differentiation; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000628:therapy; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology* / Q000378:metabolism*; D016381:Islets of Langerhans Transplantation; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009940:Organoids / Q000166:cytology / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D007328:Insulin; D005947:Glucose