Hypothyroidism impairs human stem cell-derived pancreatic progenitor cell maturation in mice

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. However, it remains unclear how the milieu of pancreatic progenitor cells, including exposure to different factors following transplant, may influence their maturation. Here, we examined the impact 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 macro-encapsulated hESC-derived progenitor cells and thyroid dysfunction was maintained either for the duration of the study (‘chronic’) or for 4-weeks post-transplant (‘acute’). Acute hyperthyroidism did not affect graft function, but acute hypothyroidism transiently impaired human C-peptide secretion at 16 weeks post-transplant. 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. Taken together, these data suggest that long-term thyroid hormone deficiency may drive the differentiation of pancreatic progenitor cells towards α- and e-cell lineages at the expense of β-cell formation.