title: 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.affiliation: Laboratory of Molecular and Cellular Medicine, Department of Cellular & Physiological Sciences, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Bruin
authors.affiliation: Laboratory of Molecular and Cellular Medicine, Department of Cellular & Physiological Sciences, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Nelly
authors.initials: N
authors.lastname: Saber
authors.affiliation: Laboratory of Molecular and Cellular Medicine, Department of Cellular & Physiological Sciences, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Shannon
authors.initials: S
authors.lastname: O'Dwyer
authors.affiliation: Laboratory of Molecular and Cellular Medicine, Department of Cellular & Physiological Sciences, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Fox
authors.affiliation: Laboratory of Molecular and Cellular Medicine, Department of Cellular & Physiological Sciences, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Majid
authors.initials: M
authors.lastname: Mojibian
authors.affiliation: BetaLogics Venture, Janssen R&D, LLC, Raritan, NJ.
authors.forename: Payal
authors.initials: P
authors.lastname: Arora
authors.affiliation: BetaLogics Venture, Janssen R&D, LLC, Raritan, NJ.
authors.forename: Alireza
authors.initials: A
authors.lastname: Rezania
authors.affiliation: Laboratory of Molecular and Cellular Medicine, Department of Cellular & Physiological Sciences, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada Department of Surgery, The University of British Columbia, Vancouver, British Columbia, Canada tim.kieffer@ubc.ca.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kieffer
mesh_terms: D000818:Animals; D013956:Antithyroid Agents / Q000506:poisoning; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D018914:Cells, Immobilized / Q000166:cytology / Q000473:pathology / Q000637:transplantation; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D004195:Disease Models, Animal; D064593:Heterografts / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D000066449:Human Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D006801:Humans; D006980:Hyperthyroidism / Q000139:chemically induced / Q000150:complications; D007037:Hypothyroidism / Q000150:complications* / Q000209:etiology; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D007455:Iodine / Q000172:deficiency; D008297:Male; D016513:Mice, SCID; D011441:Propylthiouracil / Q000506:poisoning; D011897:Random Allocation; D013974:Thyroxine / Q000506:poisoning; D014183:Transplantation, Heterologous; D016042:Transplantation, Heterotopic
chemical_list: D013956:Antithyroid Agents; D015415:Biomarkers; D011441:Propylthiouracil; D007455:Iodine; D013974:Thyroxine