Glycogen synthase kinase 3, originally described for its effects on inactivating glycogen synthase, has emerged as a regulator of several divergent signaling pathways. More recently, its activity has been implicated in hematopoietic stem cell (HSC) function, and the work presented in this paper focuses on the effect of its activity on hematopoietic stem cell recovery. In a mouse model, the investigators used an ATP binding inhibitor of GSK (CHIR-911) to demonstrate the critical role of this enzyme in HSC function. GFP-labeled donor cells were transferred into sublethally irradiated recipient mice and those in which GSK activity was inhibited demonstrated doubling of the HSC population. The repopulating cells were able to reconstitute multiple hematopoietic cell lineages, and the distribution among the lineages, when compared to untreated mice, was not affected by the inhibitor. Furthermore, when peripheral counts were examined, both the neutrophil and platelet counts increased at two and four weeks after transplant and HSC repopulation was maintained for at least 11 weeks. The GSK-3 inhibitor affects the number of primitive hematopoietic cells by enhancing proliferation rather than affecting apoptosis; this occurs through a direct effect on the HSC rather than modulating the microenvironment. Using this model, the investigators were also able to show that human HSC reconstitution behaved similarly.
GSK-3 inhibitors are rapidly moving toward clinical use in diabetes and Alzheimer's disease. Here, the investigators put forth yet another potential role for this class of drugs and one that may work at several different branch points in bone marrow transplant. The time to engraftment, as measured by the appearance of platelets and neutrophils in the circulating blood, is shortened when mice are treated with this class of inhibitors. Treatment with this drug has the potential not only to overcome situations where collection of HSC may be suboptimal, but also to enable an approach where fewer cells are needed for collection. Whether this strategy has broader application to early progenitors where specific genetic material has been introduced to overcome a genetic defect and whether this can somehow enhance or sustain production of a population of cells will remain to be seen.
The inhibitor of GSK-3 used in these studies was shown to affect a number of pathways that include Hedgehog, Notch, and Wnt. The data presented in the manuscript add some conflicting information to the field in that the inhibitor activates Notch and Wnt signaling in primitive cells, but at least with Wnt, one of its downstream target genes is downregulated. It has been established that disruption of these pathways does not affect HSC function. Thus, although these pathways can be modulated by treatment of hematopoietic precursor cells with an inhibitor of GSK-3, it remains to be established whether its effects are through these pathways in the HSC, whether there are other important pathways to be delineated that are affected by GSK-3, and where in the development of the HSC GSK-3 is acting. Examination of other inhibitors of this enzyme may shed light on what pathways are critical to the observed effect on hematopoietic stem cells. Although the picture is not complete, it remains intriguing to pursue a class of drugs that may yield a tool that not only affects the time to engraftment but also may overcome the need for collection of large numbers of cells and may shorten engraftment so that the risk of morbidity from infection is reduced.
Competing Interests
Dr. Petruzzelli indicated no relevant conflicts of interest.
