The dysregulation of high glucose-induced iPSC-neural stem cells differentiation by caspase-1.

Abstract

Maternal diabetes (MD) increases the risk for neurodevelopmental disorders and leads to neural tube defects (NTDs) which are severe anomalies of the nervous system. In order to elucidate the etiology and pathological mechanisms causing NTDs in MD and try to search for new therapeutic strategies as well, the exposure of induced pluripotency stem cell (iPSC)-neural stem cells (NSCs) to high glucose (HG) may be associated with fetal progressive deterioration of neuronal functions in utero ultimately leading to MD-related NTDs. In the present study, although HG (25 mM) had no effect on the viability of undifferentiated iPSC-NSCs compared with the positive control mannitol (25 mM), HG attenuated iPSC-NSCs cell proliferation and induced the presence of decreased βIII-tubulin and neurite network length during 7-day neuronal differentiation, resulting in the inability of nerve-to-nerve connections to communicate effectively. Compared with mannitol, HG actually reduced gene and protein expressions of iPSC-NSCs differentiation marker βIII-tubulin on day 7. Moreover, HG increased protein expressions of caspase-1 during 7-day neuronal differentiation compared with mannitol, indicating the critical role of caspase-1 in HG-mediated neuronal inflammation. Thus, the present study indicated that HG-induced impairment in iPSC-NSCs differentiation was mediated by decreased βIII-tubulin, shorter neurite network length and increased caspase-1 expressions, which provided a direction for the clarification of MD-induced NTDs.