Ephrin Signaling and Restored Activity in Tendon Stem Cells
Many research groups are looking for protein levels and mechanisms that act as regulators or proximate causes of age-related reductions in stem cell activity. Here is one example, focused on tendon tissue:
Aged or degenerated tendons respond poorly to classical medicinal treatments, which often leads to rupture reoccurrence. Until now, several major factors contributing, directly, or indirectly, to tendon aging and degeneration were identified: disturbance of extracellular matrix turnover; decreasing cell numbers and metabolic activity; tenocyte dedifferentiation; and depletion or senescence of the local stem/progenitor cell pool. Tendon stem/progenitor cells (TSPCs) were first reported in 2007 as as plastic adherent cells that express classical stem cell markers while maintaining the expression of typical tendon-lineage genes. It was proposed that tendon healing is carried out mainly by such local tendon progenitor cells, which actively migrate to the wound site and engage in cell proliferation. However, TSPC features alter during tendon aging and degeneration. Aged TSPC display a profound self-renewal deficit accompanied with premature entry into senescence and substantial changes in their transcriptome. Furthermore these cells exhibit severely dysregulated cell-matrix interactions, motility and actin dynamics.In the current study, we report for the first time that aged TSCP have dysregulated cell-cell interactions mediated by the ephrin family. By comparing young to aged TPSC we found that the expression of several ephrin members is significantly changed. Next, by carefully examining the role of two main candidates, namely the receptors EphA4 and EphB2, we could demonstrate that by activating their reverse signaling we can normalize several of the aged TSCP deficits, the migratory ability and actin turnover. However, only EphA4 stimulation improved aged TSPC cell proliferation to levels comparable to young TSPC. We propose that dysregulation in EphA4-triggered bi-directional signaling may contribute to the inferior and delayed tendon healing common for aged individuals, which will be the focus for upcoming investigation.