Mouse embryonic stem cells lacking p38α and p38δ 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, p38α, p38β, p38γ, and p38δ, have been identified in mammalian cells. Previous studies have shown that p38α knockout is embryonic lethal in mice. At the cellular level, p38α is abundantly expressed in mouse embryonic stem cells (ESCs), but p38α knockout (p38α-/-) ESCs can differentiate to endothelial cells (ECs), smooth muscle cells (SMCs), and neurons. We speculate that the lost function of p38α in p38α-/- ESCs may be compensated for by the redundant function of other isoforms. To test this hypothesis, we used siRNA approach to knock down the expression of p38δ, the second abundant isoform in ESCs. ESCs stably expressing p38δ siRNA were established from p38α-/- ESCs, resulting in 80% reduction of p38δ mRNA expression. However, these ESCs, deficient of both p38α and p38δ, could still differentiate into ECs and SMCs. We extended our investigation to test if these cells can differentiate into epithelial cells in which p38δ has been shown to regulate epidermis differentiation. Our results demonstrate again that ESC differentiation to epithelial cells is independent of p38α and p38δ. We conclude that p38α and p38δ 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.