Correspondence on “Microgravity Reduces the Differentiation and Regenerative Potential of Embryonic Stem Cells”

Editor: One of the major advances in developmental biology of the past decade is the recognition that multiple stem cell compartments exist that to a certain extent are hierarchically organized and have different tissue regenerating capacities and molecular identities. Consequently, understanding the molecular and physical factors that determine stem cell identity has now become a major research question in the field [1]. A problem encountered in addressing such questions is that it is technically sometimes very challenging to isolate the influence of certain physical or molecular traits from the milieu exterieur in its entirety as to allow reductionistic experimentation addressing the influence of such factors on stem cell identity. A case in the point is gravity. The mechanical loading of cells resulting from gravity is obviously affecting all stem cells on the planet, but the influence of this force on stem cell identity is difficult to establish. In this sense, the recent study published in Stem Cells and Development by Blaber et al. [2], in which space flight is used to investigate the influence of gravity on murine embryonic stem identity, is very welcome and timely. Remarkably, the authors demonstrate that mechanical unloading provokes increased stemness and counteracts differentiation and regenerative responses of embryoid bodies derived from murine embryonic stem cells. The study demonstrates the importance of such studies addressing the influence of specific physical factors on stem cell identity being carried out.

The authors stop short, however, from addressing the molecular signal transduction pathways mediating these effects of microgravity. Various pathways are discussed in the study, including cell cycle and DNA damage pathways, Wnt signaling, and the Notch pathway, but no conclusive proof for the involvement of these pathways in the effects of mechanical unloading on stem cell properties, either from experimentation itself or from literature data, is presented in this study. This is a pity as we feel that the Jun-N-terminal kinase (JNK) signaling cascade would have been a fitting and also testable candidate to mediate these effects. Recently, we established that in the immune compartment, JNK is sensitive to spaceflight-induced microgravity, its activity inhibited within minutes [3]. And we are certainly not alone in our finding. Various studies on (artificial) microgravity did similar observations in other cell compartments, perhaps suggesting a more general mechanism. Where microgravity represents a condition in which the continuous presence of gravitational force is absent, mechanical stress can be considered the opposite in which increased forces are applied to a cell. It is widely accepted that mechanical stress induces integrin-mediated JNK activation with the authors themselves among the first to attribute an important role to JNK with respect to the axis for adhesion survival mechanotransduction [4]. Strikingly, Kim et al. demonstrated in a model not unlike that employed by Blaber et al. that inhibition of JNK signaling is required for maintaining stemness [5]. We thus feel it imperative that future studies address the role of the JNK signaling cascade in the effect of mechanical unloading on stemness per se and stem cell identity in general.