First generation stem cell therapies are highly variable. While they fairly reliably suppress chronic inflammation for a time, other benefits vary widely from clinic to clinic and approach to approach. In part this may be because cells are hard to manage. Small differences in protocol, even unintentional differences, can produce large differences in outcome. Of late, researchers have started to ask whether variations in cell therapy outcomes may be in part mediated by a large variability in the degree to which cells become senescent in culture during the preparation for injection. Only a tiny proportion of cells need to be senescent in order to produce detrimental effects on the others. Thus researchers are now investigating the use of senolytics and other means as a way to improve the quality of this class of cell therapy.
Mesenchymal stem cells (MSCs) are recognized as potential treatments for multiple degenerative and inflammatory disorders as a number of animal and human studies have indicated their therapeutic effects. There are also several clinically approved medicinal products that are manufactured using these cells. For such large-scale manufacturing requirements, the in vitro expansion of harvested MSCs is essential. Multiple subculturing of MSCs, however, provokes cellular senescence processes which is known to deteriorate the therapeutic efficacy of the cells. Strategies to rejuvenate or selectively remove senescent MSCs are therefore highly desirable for fostering future clinical applications of these cells.
In this present study, we investigated gene expression changes related to cellular senescence of MSCs derived from umbilical cord blood and found that CD26, also known as DPP4, is significantly upregulated upon cellular aging. We further observed that the inhibition of CD26 by genetic or pharmacologic means delayed the cellular aging of MSCs with their multiple passaging in culture. Moreover, the sorting and exclusion of CD26-positive MSCs from heterogenous cell population enhanced in vitro cell attachment and reduced senescence-associated cytokine secretion. CD26-negative MSCs also showed superior therapeutic efficacy in a mouse model of lung emphysema. Our present results collectively suggest CD26 is a potential novel target for the rejuvenation of senescent MSCs for their use in manufacturing MSC-based applications.