Hematopoietic stem cell transplantation is possible because progenitors and stem cells have the ability to home to their niches to re-establish normal hematopoiesis. This is a highly orchestrated process that requires specific homing receptor-ligand interactions. Imagine that one of these stems cells is plucked out in a bone marrow harvest and then re-infused into a central vein. That cell will circulate in the vasculature until it finds the appropriate receptors. Cellular recruitment to bone occurs within specialized marrow vessels that constitutively express vascular E-selectin, a lectin that recognizes specific sugars (sialofucosylated determinants) on its various ligands. Then that cell has to transmigrate from the vascular endothelium into the interstitial space and again into the bone marrow cavity and find the proper niche. There it will be able to self-renew and also differentiate into committed progenitors. If that cell is not able to find the appropriate niche, it is likely to die or possibly remain quiescent, unable to provide the necessary contribution to hematopoietic reconstitution. Similarly, other adoptive cellular therapies (i.e., antigen-specific T cells) rely on the potential that the infused cells will home to the appropriate sites for their effector function. But how do they find the right home?
The publication by Sackstein, et al. demonstrates the importance and potential clinical application of ensuring the proper address. Multipotent mesenchymal stromal cells (MSCs, also termed mesenchymal stem cells) have the potential for a variety of therapeutic uses. However, clinically their use is constrained by the poor osteotropism of infused MSCs. Human MSCs do not express E-selectin ligands, but express a CD44 glycoform bearing α-2,3-sialyl modifications. Using an α-1,3-fucosyltransferase preparation and enzymatic conditions specifically designed for treating live cells, they converted the native CD44 glycoform on MSCs into hematopoietic cell E-selectin/L-selectin ligand (HCELL), which conferred potent E-selectin binding without effects on cell viability or multipotency. Real-time intravital microscopy in immunocompromised (NOD/SCID) mice showed that intravenously infused HCELL+ MSCs infiltrated marrow within hours of infusion, with ensuing rare foci of endosteally localized cells and human osteoid generation. Following extravasation, there was reversion to the native CD44 glycoform.
In Brief
The ability to modify the decorated sugars on the cell surface without changes in multipotency or survival is an exciting finding and raises the prospect for clinical application. Despite the lack of the necessary effectors for homing to bone, osteotropism was conferred by ex vivo modification of the sugars of a single glycoprotein (CD44) creating a potent E-selectin ligand HCELL. Engineering HCELL expression was achieved by rational design to specifically drive surface α-1,3-fucosylation. Therefore, this technology could significantly improve the use of MSCs for hematopoietic reconstitution. Moreover, E-selectin expression is upregulated in areas of inflammation and ischemia; therefore, programmed HCELL expression should provide the proper address for targeted migration and infiltration of these cells for therapeutic purposes. In a broader sense, increasing E-selectin ligand activity could be expanded to other populations of cells. A variety of physiologic and pathologic processes, including immune diseases, infectious diseases, and cancer, are accompanied by upregulated E-selectin expression in affected endothelial beds. Regulatory T cells or cytotoxic T cells could be programmed for specific cellular trafficking by chemical modification of their cell surface sugars on a distinct membrane glycoprotein.
Who says you can't go home again?
Competing Interests
Dr. Chao indicated no relevant conflicts of interest.
