Modulation of the neural lineage entry of mouse embryonic stem cells by the CD38/cADPR/Ca2+ signaling pathway

Abstract

The in vitro generation of neural lineage cells from embryonic stem (ES) cells is a promising approach to produce cells suitable for neural tissue repair and cell-based replacement therapies of the nervous system. Here we explore the role of one endogenous Ca2+ mobilizing nucleotide, cyclic adenosine diphosphoribose (cADPR), in the neural differentiation of mouse ES cells. cADPR is present in many cell types and different species, from plants to animals, and plays an important role in a wide variety of cellular processes. cADPR is formed by ADP-ribosyl cyclases from nicotinamide adenine dinucleotide (NAD). The main ADP-ribosyl cyclase in mammals is CD38, a multi-functional enzyme and a type II membrane protein. We found that the expression of CD38 is decreased during the neural differentiation of mouse ES cells in vitro. Perturbing the CD38/cADPR signaling by either CD38 knockdown or treatment with a cADPR antagonist, 8-Br-cADPR, promoted the neural commitment of mouse ES cells. We hypothesize that the CD38/cADPR-mediated Ca2+ signaling pathway antagonizes the neural lineage entry of mouse ES cells. We are currently examining the molecular mechanisms of cADPR signaling in the neural commitment of mouse ES cells.