Neural tube defects (NTDs) are among the most common and severe structural birth defects and maternal diabetes induces NTDs. During mouse embryonic development, blood vessel formation initially occurs in the yolk sac, preceding neurulation which takes place from embryonic day 8 (E8) to E10.5. Our previous studies have demonstrated that maternal diabetes induces embryonic vasculopathy at early embryonic developmental stage. We hypothesize that early vasculopathy accounts for late failed neural tube closure in diabetic pregnancy. To test this hypothesis, we created the Flk1 promoter driven survivin (the cell cycle-regulated apoptosis inhibitor) transgenic mice. Maternal diabetes induced the loss of Flk1+ progenitors, impaired blood island formation and reduced blood vessel densities. Expression of survivin in the Flk1+ progenitors ameliorated diabetes-induced NTDs. Under nondiabetic conditions, survivin overexpression did not affect embryonic development. Overexpression of survivin significantly reduced diabetes-induced NTDs. Flk1+ progenitors produced survivin-containing exosomes. Immunocytochemistry staining indicated that survivin-containing exosomes were transported and incorporated into cells of the developing neuroepithelium, leading to blockage of neuroepithelial cell apoptosis induced by maternal diabetes. Furthermore, we isolated exosomes from Flk1+ progenitors derived from E7.5 embryos. In utero delivery of the survivin-containing exosomes by microinjection into the amniotic cavity of diabetic mice at E9 significantly inhibited maternal diabetes-induced neuroepithelial cell apoptosis and reduced NTDs. Taken together, these data revealed that the cross-talk between the extra-embryonic structures and the developing neuroepithelium through the survivin-containing exosome plays a critical role for the proper neural tube closure.


S. Cao: None. W. Shen: None. P. Yang: None.

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