Abstract
Various types of progenitors initiate individual organ formation and their crosstalk orchestrates morphogenesis for the entire embryo. Here we show that progenitor exosomal communication across embryonic organs occurs in normal development and is altered in embryos of diabetic pregnancy. Endoderm fibroblast growth factor 2 (FGF2) stimulates mesoderm Flk-1+ vascular progenitors to produce exosomes containing the anti-stress protein Survivin. These exosomes act on neural stem cells of the neuroepithelium to facilitate neurulation by inhibiting cellular stress and apoptosis. Maternal diabetes causes Flk-1+ progenitor dysfunction by suppressing FGF2 through DNA hypermethylation. Restoring endoderm FGF2 prevents diabetes-induced survivin reduction in Flk-1+ progenitor exosomes. Transgenic Survivin expression in Flk-1+ progenitors or in utero delivery of survivin-enriched exosomes restores cellular homeostasis and prevents diabetes-induced neural tube defects (NTDs), whereas inhibiting exosome production induces NTDs. Thus, functional inter-organ communication via Flk-1 exosomes is vital for neurulation and its disruption leads to embryonic anomalies.