Composition and function of macroencapsulated human embryonic stem cell-derived implants: comparison with clinical human islet cell grafts

American Journal of Physiology - Endocrinology and Metabolism - Tập 307 Số 9 - Trang E838-E846 - 2014
Evi Motté1, Edit Szepessy1, Krista Suenens1, Geert Stangé1, Myriam Bomans2, Daniel Jacobs‐Tulleneers‐Thevissen1, Zhidong Ling1, Evert Kroon3, Daniël Pipeleers1
1Diabetes Research Center, Brussels Free University-Vrije Universiteit Brussel, Brussels, Belgium;
2Beta-Cell NV, Brussels, Belgium; and
3ViaCyte Incorporated, San Diego, California

Tóm tắt

β-Cells generated from large-scale sources can overcome current shortages in clinical islet cell grafts provided that they adequately respond to metabolic variations. Pancreatic (non)endocrine cells can develop from human embryonic stem (huES) cells following in vitro derivation to pancreatic endoderm (PE) that is subsequently implanted in immune-incompetent mice for further differentiation. Encapsulation of PE increases the proportion of endocrine cells in subcutaneous implants, with enrichment in β-cells when they are placed in TheraCyte-macrodevices and predominantly α-cells when they are alginate-microencapsulated. At posttransplant (PT) weeks 20–30, macroencapsulated huES implants presented higher glucose-responsive plasma C-peptide levels and a lower proinsulin-over-C-peptide ratio than human islet cell implants under the kidney capsule. Their ex vivo analysis showed the presence of single-hormone-positive α- and β-cells that exhibited rapid secretory responses to increasing and decreasing glucose concentrations, similar to isolated human islet cells. However, their insulin secretory amplitude was lower, which was attributed in part to a lower cellular hormone content; it was associated with a lower glucose-induced insulin biosynthesis, but not with lower glucagon-induced stimulation, which together is compatible with an immature functional state of the huES-derived β-cells at PT weeks 20–30. These data support the therapeutic potential of macroencapsulated huES implants but indicate the need for further functional analysis. Their comparison with clinical-grade human islet cell grafts sets references for future development and clinical translation.

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Thông tin
Thông tin xuất bản

American Journal of Physiology - Endocrinology and Metabolism

Tập 307 Số 9

E838-E846

Thông tin tác giả