Hypothyroidism Impairs Human Stem Cell-Derived Pancreatic Progenitor Cell Maturation in Mice.

Abstract

Pancreatic progenitors derived from human embryonic stem cells (hESCs) are a potential source of transplantable cells for treating diabetes and are currently being tested in clinical trials. Yet, how the milieu of pancreatic progenitor cells, including exposure to different factors after transplant, may influence their maturation remains unclear. Here, we examined the effect of thyroid dysregulation on the development of hESC-derived progenitor cells in vivo. Hypothyroidism was generated in SCID-beige mice using an iodine-deficient diet containing 0.15% propyl-2-thiouracil, and hyperthyroidism was generated by addition of L-thyroxine (T4) to drinking water. All mice received macroencapsulated hESC-derived progenitor cells, and thyroid dysfunction was maintained for the duration of the study ("chronic") or for 4 weeks posttransplant ("acute"). Acute hyperthyroidism did not affect graft function, but acute hypothyroidism transiently impaired human C-peptide secretion at 16 weeks posttransplant. Chronic hypothyroidism resulted in severely blunted basal human C-peptide secretion, impaired glucose-stimulated insulin secretion, and elevated plasma glucagon levels. Grafts from chronic hypothyroid mice contained fewer β-cells, heterogenous MAFA expression, and increased glucagon(+) and ghrelin(+) cells compared to grafts from euthyroid mice. Taken together, these data suggest that long-term thyroid hormone deficiency may drive the differentiation of human pancreatic progenitor cells toward α- and ε-cell lineages at the expense of β-cell formation.

• Authors: Jennifer E Bruin, Nelly Saber, Shannon O'Dwyer, Jessica K Fox, Majid Mojibian, Payal Arora, Alireza Rezania, Timothy J Kieffer
• Journal: Diabetes (Diabetes) Vol. 65 Issue 5 Pg. 1297-309 (05 2016) ISSN: 1939-327X [Electronic] United States
• PMID: 26740603 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Chemical References

• Antithyroid Agents
• Biomarkers
• Propylthiouracil
• Iodine
• Thyroxine

Topics

• Animals
• Antithyroid Agents (poisoning)
• Biomarkers (blood, metabolism)
• Cell Differentiation
• Cell Line
• Cells, Immobilized (cytology, pathology, transplantation)
• Diabetes Mellitus, Type 1 (complications, metabolism, pathology, surgery)
• Disease Models, Animal
• Heterografts (cytology, metabolism, pathology)
• Human Embryonic Stem Cells (cytology, metabolism, pathology, transplantation)
• Humans
• Hyperthyroidism (chemically induced, complications)
• Hypothyroidism (complications, etiology)
• Insulin-Secreting Cells (cytology, metabolism, pathology, transplantation)
• Iodine (deficiency)
• Male
• Mice, SCID
• Propylthiouracil (poisoning)
• Random Allocation
• Thyroxine (poisoning)
• Transplantation, Heterologous
• Transplantation, Heterotopic