Stromal cell-secreted factors promote the survival of embryonic stem cell-derived early neural stem/progenitor cells via the activation of MAPK and PI3K-Akt pathways

Neural stem/progenitor cells (NS/PCs) have been studied extensively with the hope of using them clinically to repair the damaged central nervous system. However, little is known about the signals that regulate the proliferation, survival, and differentiation of NS/PCs in early development. To clarify the underlying mechanisms, we took advantage of an in vitro ES cell differentiation system from which we can obtain neurospheres containing NS/PCs with characteristics of the early caudal neural tube, by treating embryoid bodies (EBs) with a low concentration of retinoic acid (RA). We found that conditioned medium from the PA6 stromal cell line (PA6CM) increased the efficiency of neurosphere formation by suppressing apoptosis and promoting the survival of the NS/PCs. PA6CM also induced the phosphorylation of Erk1/2 and Akt1 in cells derived from the EBs. Furthermore, inhibitors of the MAPK and PI3K-Akt signaling pathways, U0126 and LY294002, attenuated the effects of PA6CM, significantly increasing the number of apoptotic cells and decreasing the number of viable cells among the ES cell-derived NS/PCs. Thus, PA6CM appears to contain soluble factors that promote the survival of ES cell-derived early NS/PCs through the activation of the MAPK and PI3K-Akt pathways.