Objective Human astrocytes and human neurons were transfected with EIF2B5-RNAi vectors or blank as cell model to investigate the causes that white matter glial cells selectively involved in vanishing white matter disease.Methods Apoptosis and cell viability were measured in human astrocytes and neurons with EIF2B5-RNAi or blank vector before or after the stimulation of endoplasmic reticulum stress (ERS). The sequence of known and unknown microRNAs was performed to screen those participated in regulating the response of ERS.Results Under the baseline condition, apoptosis rates were detected higher in human astrocytes with EIF2B5-RNAi and cell viability decreased significantly than the wild-type and neurons. More pieces of miRNAs regulated the ERS rescue in astrocytes with blank vectors than the EIF2B5-RNAi group. In the cluster analysis, 5 pieces of miRNAs were identified as key components in pathway network.Conclusion The recovery of human astrocytes from ERS may be more dependent on the numerous miRNAs than neurons for cell proliferation and differentiation. The eroded clusters of miRNAs may promote spontaneous apoptosis and cell viability decrease in human astrocytes with EIF2B5-RNAi. As a result, it reduced the chance of survival in human astrocytes with EIF2B5-RNAi after ERS crisis.