β1-Adrenoceptor stimulation enhances the differentiation of mouse induced pluripotent stem cells into neural progenitor cells

The cyclic AMP/protein kinase A signaling pathway is thought to be involved in neural differentiation of mesenchymal stem cells. In the present study, we examined the involvement of beta-adrenoceptor signaling on the differentiation of mouse induced pluripotent stem (iPS) cells into neural progenitor cells. Mouse iPS cells were cultured on ultra-low-attachment dishes to induce embryoid body (EB) formation. All-trans retinoic acid (ATRA, 1 mu M) and/or the beta-adrenoceptor agonist L-isoproterenol (0.3 or 1 mu M) were added to the EB cultures for 4 days, then EBs were plated on gelatin-coated plates and cultured for 7 or 14 days. Subtype-specific antibody staining revealed that mouse iPS cells express beta(1)-adrenoceptors predominantly. Although treatment with L-isoproterenol alone did not affect the expression of Nestin (a specific marker for neural progenitor cells), L-isoproterenol significantly enhanced ATRA-induced Nestin expression. Pretreatment of EBs with either atenolol (a selective beta(1)-adrenoceptor antagonist) or H89 (a protein kinase A inhibitor) significantly inhibited the L-isoproterenol-enhancement of ATRA-induced Nestin expression. In addition, the L-isoproterenol treatment significantly enhanced ATRA-induced expression of NeuN (a neuron-specific nuclear protein). These findings suggest that beta(1)-adrenoceptor stimulation enhances ATRA-induced neural differentiation of mouse iPS cells. (c) 2012 Elsevier Ireland Ltd. All rights reserved.