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.
Highlights
The islets of Langerhans, a pancreatic endocrine tissue, are composed of insulin-producing ß cells, glucagon-producing αcells, somatostatin-producing δcells, pancreatic peptide-producing PP cells, and ghrelin-producing εcells[24,25,26,27,28]
Based on previous reports[12,13,14,15,16,34,35], efficient protocols for differentiating hESCs into pancreatic endocrine cells have been re-established in this study (Fig. 1a)
endocrine cell clusters (ECCs) were generated from hESC-derived Endocrine cells (ECs), and their functionalities were examined in vitro and in vivo
Summary
The islets of Langerhans, a pancreatic endocrine tissue, are composed of insulin-producing ß cells, glucagon-producing αcells, somatostatin-producing δcells, pancreatic peptide-producing PP cells, and ghrelin-producing εcells[24,25,26,27,28]. Thereafter, endocrine cells in the pancreatic islets play roles in the regulation of blood glucose levels. Reciprocal interactions among endocrine cells in the islets are critical for the regulation of insulin secretion in response to glucose. The interplay between ß cells through gap junctions synchronizes heterogeneous glucose responsiveness; pancreatic endocrine hormones secreted from δand αcells regulate insulin secretion from ß cells[31,32,33]. Pancreatic islet structures would be effective means of physiologically regulating insulin secretion. We demonstrate that pancreatic islet-like clusters generated from hESCs functionally secrete insulin. HPSC-derived ECCs exhibited ß cell-like functions both in vitro and in vivo. Our results indicate that hPSC-derived ECCs can effectively secrete insulin for the treatment of diabetes
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