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

Abstract

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 how to separately derive lung vs. thyroid epithelial lineages, since 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 prior reports. Here we employ PSCs to identify the key minimal signaling pathways (Wnt+BMP vs. BMP+FGF) that regulate distinct lung vs. thyroid lineage specification, respectively, from foregut endoderm. In contrast to most prior reports these minimal pathways appear to be evolutionarily conserved between mice and humans, and FGF signaling, while 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.