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

Am J Physiol Endocrinol Metab. 2014 Nov 1;307(9):E838-46. doi: 10.1152/ajpendo.00219.2014. Epub 2014 Sep 9.

Abstract

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.

Keywords: cell therapy; encapsulation; human embryonic stem cells; insulin synthesis and release.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • C-Peptide / blood
  • C-Peptide / metabolism
  • Cell Differentiation
  • Cell Line
  • Cells, Immobilized / cytology
  • Cells, Immobilized / metabolism
  • Cells, Immobilized / transplantation*
  • Crosses, Genetic
  • Diabetes Mellitus, Type 1 / blood
  • Diabetes Mellitus, Type 1 / metabolism
  • Diabetes Mellitus, Type 1 / pathology
  • Diabetes Mellitus, Type 1 / surgery*
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism
  • Embryonic Stem Cells / transplantation*
  • Glucagon-Secreting Cells / cytology
  • Glucagon-Secreting Cells / metabolism
  • Humans
  • Implants, Experimental / adverse effects*
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / metabolism
  • Islets of Langerhans Transplantation / adverse effects*
  • Kidney
  • Membranes
  • Mice, Inbred NOD
  • Mice, SCID
  • Proinsulin / blood
  • Proinsulin / metabolism
  • Subcutaneous Tissue
  • Tissue Scaffolds / adverse effects
  • Transplantation, Heterologous / adverse effects*
  • Transplantation, Heterotopic / adverse effects*

Substances

  • C-Peptide
  • Proinsulin