Mouse embryonic stem cells lacking p38 alpha and p38 delta can differentiate to endothelial cells, smooth muscle cells, and epithelial cells
The p38 mitogen-activated protein (MAP) kinases (p38) are important signaling molecules that regulate various cellular processes. Four isoforms of p38 family, p38 alpha, p38 beta, p38 gamma, and p38 delta, have been identified in mammalian cells. Previous studies have shown that p38 alpha knockout is embryonic lethal in mice. At the cellular level, p38a is abundantly expressed in mouse embryonic stem cells (ESCs), but p38 alpha knockout (p38 alpha-/-) ESCs can differentiate to endothelial cells (ECs), smooth muscle cells (SMCs), and neurons. We speculate that the lost function of p38 alpha in p38 alpha-/- ESCs may be compensated for by the redundant function of other isoforms. To test this hypothesis, we used siRNA approach to knockdown the expression of p38 delta, the second abundant isoform in ESCs. ESCs stably expressing p38 delta siRNA were established from p38 alpha-/- ESCs, resulting in 80% reduction of p38 delta mRNA expression. However, these ESCs, deficient of both p38 alpha and p38 delta, could still differentiate into ECs and SMCs. We extended our investigation to test if these cells can differentiate into epithelial cells in which p38 delta has been shown to regulate epidermis differentiation. Our results demonstrate again that ESC differentiation to epithelial cells is independent of p38 alpha and p38 delta. We conclude that p38 alpha and p38 delta are not essential for ESC differentiating into ECs, SMCs, or epithelial cells although numerous studies have shown that the two kinases regulate various cellular activities in aforementioned cells. Our results highlight the possibility that p38 MAP kinases may play less significant roles in ESC differentiation than in the regulation of cellular activities of fully differentiated somatic cells. (C) 2009 International Society of Differentiation. Published by Elsevier Ltd. All rights reserved.