By Nelson Chao, MD
2008-09-01
Dr. Chao indicated no relevant conflicts of interest.
Sackstein R, Merzaban JS, Cain DW, et al. Ex vivo glycan engineering of CD44 programs human multipotent mesenchymal stromal cell trafficking to bone. Nat Med. 2008;14:181-7.
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.
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?
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