The many faces of p38 mitogen-activated protein kinase in progenitor/stem cell differentiation

Regulation of stem cells is essential for development and adult tissue homoeostasis. The proper control of stem cell self-renewal and differentiation maintains organ physiology, and disruption of such a balance results in disease. There are many mechanisms that have been established as stem cell regulators, such as Wnt or Notch signals. However, the intracellular mechanisms that mediate and integrate these signals are not well understood. A new intracellular pathway that has been reported to be involved in the regulation of many stem cell types is that of p38 MAPK (mitogen-activated protein kinase). In particular, p38α is essential for the proper differentiation of many haematopoietic, mesenchymal and epithelial stem/progenitor cells. Many reports have shown that disruption of this kinase pathway has pathological consequences in many organs. Understanding the extracellular cues and downstream targets of p38α in stem cell regulation may help to tackle some of the pathologies associated with improper differentiation and regulation of stem cell function. In the present review we present a vision of the current knowledge on the roles of the p38α signal as a regulator of stem/progenitor cells in different tissues in physiology and disease.