The Many Functions of Fucose: Uncovering the Sugar's Central Role in Successful Stem Cell Transplantation

Fucose is emerging as a wonder glycan for improving the success of hematopoietic stem cell (HSC) transplantation in bone marrow, with implications for a broad range of diseases especially those relating to blood. When the sugar is added to the surface of stem cells via α1,3-fucosylation treatment, several studies, including our own, have demonstrated that the HSCs gain navigation capacity: more of them reach the bone marrow and are able to home and engraft within it. But there are other, less understood ways that demonstrate how fucose could potentially transform the success of HSC transplantation.

The first of these is the central role of fucose in HSC cell rolling. We found that treatment with α1,3-fucosylation led to a 1.4-fold increase in the number of rolling cells, compared with untreated controls. Meanwhile, when cells were treated with a fucosylation inhibitor (2-fluorofucose), this led to a 2.7-fold decrease in the number of rolling cells. Aside from the quantity, fucosylation also made HSCs better at rolling because they developed longer tethers and slings that allow tighter binding to the bone marrow homing receptor E-selectin, according to in vitro live cell imaging flow-based assays. They had a higher propensity to reach the bone marrow and spleen of immuno-compromised mice, as shown by in vivo xenotransplantation studies. By contrast, inhibiting fucosylation had the opposite effect on cells: in vitro they showed shorter tethers and slings; while in vivo, fewer HSCs reached the bone marrow and spleen.

A second significant finding of our research is that transplantation of HSCs into the bone marrow is more likely to succeed if they have been treated with α1,3-fucosylation. This is because the addition of fucose enhances HSC binding to E-selectin and promotes cell cycling that favors sustained generation of HSCs over time when compared with untreated controls. In fact, we noticed a two-fold increase in long-term stem cell engraftment (12-16 weeks post-transplantation) in mouse and human blood cells in murine models. Engraftment persisting beyond 12 weeks indicates that the transplanted cells include true HSCs capable of long-term self-renewal and differentiation. This is important because it addresses one of the reasons why bone marrow transplants fail, namely that the transplanted stem cell pool struggles to maintain itself for a long period of time. Improving the delivery and longevity of transplanted HSCs has important clinical applications because it opens the possibility of using cord blood or having one donor's bone marrow go further.

Another part of our research involves finding intrinsic ways to stimulate or enhance the formation of sLex on HSCs by inducing specific fucosyltransferases within them. Fucosylation works by adding a fucose to the stem cell surface to help generate Sialyl Lewis X (sLe^x), a glycan epitope that gives cells an adhesive quality that both guides them to the bone marrow and improves their engraftment. Within the cell, it is the activity of fucosyltransferase enzymes that transfers fucose to a growing glycan chain on glycoproteins and glycolipids. Understanding this mechanism, using a computational screening approach, we have identified two small molecules capable of activating a human fucosyltransferase. Our findings show that the compounds increase its activity by up to 90% in enzymatic assays and in cell lines where sLe^x creation was measured. This finding is significant because until now, studies have focused on ex-vivo fucosylation treatments to stimulate sLe^x expression on stem cells, which is limited because the effect is transient, ending once cell surface glycoproteins turn over. If we can identify and test small molecules capable of activating fucosyltransferases intrinsically in stem cells before and after transplantation, using their own endogenous machinery, this could promote a more sustained expression of sLe^x and open up a new treatment protocol to improve success rates of bone marrow transplants.

Taken together, these findings underpin the pivotal part fucose plays in cell navigation and engraftment and offer a compelling case for dedicating resources toward expediting the incorporation of fucosylation treatments at a clinical level.

No relevant conflicts of interest to declare.