Title | Thyroid Progenitors Are Robustly Derived from Embryonic Stem Cells through Transient, Developmental Stage-Specific Overexpression of Nkx2-1. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Dame K, Cincotta S, Lang AH, Sanghrajka RM, Zhang L, Choi J, Kwok L, Wilson T, Kańduła MM, Monti S, Hollenberg AN, Mehta P, Kotton DN, Ikonomou L |
Journal | Stem Cell Reports |
Volume | 8 |
Issue | 2 |
Pagination | 216-225 |
Date Published | 2017 02 14 |
ISSN | 2213-6711 |
Keywords | Animals, Bone Morphogenetic Protein 4, Cell Differentiation, Cell Line, Cell Lineage, Cluster Analysis, Embryonic Stem Cells, Fibroblast Growth Factor 2, Gene Expression, Gene Expression Profiling, Gene Expression Regulation, Developmental, Genome-Wide Association Study, Mice, Signal Transduction, Stem Cells, Thyroid Gland, Thyroid Nuclear Factor 1, Transgenes |
Abstract | The clinical importance of anterior foregut endoderm (AFE) derivatives, such as thyrocytes, has led to intense research efforts for their derivation through directed differentiation of pluripotent stem cells (PSCs). Here, we identify transient overexpression of the transcription factor (TF) NKX2-1 as a powerful inductive signal for the robust derivation of thyrocyte-like cells from mouse PSC-derived AFE. This effect is highly developmental stage specific and dependent on FOXA2 expression levels and precise modulation of BMP and FGF signaling. The majority of the resulting cells express thyroid TFs (Nkx2-1, Pax8, Foxe1, Hhex) and thyroid hormone synthesis-related genes (Tg, Tpo, Nis, Iyd) at levels similar to adult mouse thyroid and give rise to functional follicle-like epithelial structures in Matrigel culture. Our findings demonstrate that NKX2-1 overexpression converts AFE to thyroid epithelium in a developmental time-sensitive manner and suggest a general methodology for manipulation of cell-fate decisions of developmental intermediates. |
DOI | 10.1016/j.stemcr.2016.12.024 |
Alternate Journal | Stem Cell Reports |
PubMed ID | 28162994 |
PubMed Central ID | PMC5312259 |
Grant List | R35 GM119461 / GM / NIGMS NIH HHS / United States R01 DK105029 / DK / NIDDK NIH HHS / United States TL1 TR001410 / TR / NCATS NIH HHS / United States T32 HL007035 / HL / NHLBI NIH HHS / United States R01 HL095993 / HL / NHLBI NIH HHS / United States R01 HL111574 / HL / NHLBI NIH HHS / United States R01 HL122442 / HL / NHLBI NIH HHS / United States |