Pluripotent stem cell differentiation reveals distinct developmental pathways regulating lung- versus thyroid-lineage specification

Development. 2017 Nov 1;144(21):3879-3893. doi: 10.1242/dev.150193. Epub 2017 Sep 25.


The in vitro-directed differentiation of pluripotent stem cells (PSCs) through stimulation of developmental signaling pathways can generate mature somatic cell types for basic laboratory studies or regenerative therapies. However, there has been significant uncertainty regarding a method to separately derive lung versus thyroid epithelial lineages, as these two cell types each originate from Nkx2-1+ foregut progenitors and the minimal pathways claimed to regulate their distinct lineage specification in vivo or in vitro have varied in previous reports. Here, we employ PSCs to identify the key minimal signaling pathways (Wnt+BMP versus BMP+FGF) that regulate distinct lung- versus thyroid-lineage specification, respectively, from foregut endoderm. In contrast to most previous reports, these minimal pathways appear to be evolutionarily conserved between mice and humans, and FGF signaling, although required for thyroid specification, unexpectedly appears to be dispensable for lung specification. Once specified, distinct Nkx2-1+ lung or thyroid progenitor pools can now be independently derived for functional 3D culture maturation, basic developmental studies or future regenerative therapies.

Keywords: Embryo; Endoderm; Lung; Nkx2-1; Pluripotent stem cells; Thyroid.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Body Patterning* / genetics
  • Bone Morphogenetic Proteins / metabolism
  • Cell Differentiation*
  • Cell Lineage
  • Embryo, Mammalian / cytology
  • Embryonic Development
  • Endoderm / cytology
  • Endoderm / metabolism
  • Epithelial Cells / cytology
  • Fibroblast Growth Factors / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Green Fluorescent Proteins / metabolism
  • Homeodomain Proteins / metabolism
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism
  • Lung / cytology*
  • Lung / embryology*
  • Mice
  • Mouse Embryonic Stem Cells / cytology
  • Mouse Embryonic Stem Cells / metabolism
  • Pluripotent Stem Cells / cytology*
  • Reproducibility of Results
  • Signal Transduction*
  • Spheroids, Cellular / cytology
  • Spheroids, Cellular / metabolism
  • Thyroid Gland / cytology*
  • Thyroid Gland / embryology
  • Transcriptome / genetics
  • Wnt Proteins / metabolism


  • Biomarkers
  • Bone Morphogenetic Proteins
  • Homeodomain Proteins
  • Wnt Proteins
  • Green Fluorescent Proteins
  • Fibroblast Growth Factors