Ex vivo fucosylation improves human cord blood engraftment in NOD-SCID IL-2Rγ(null) mice.
Delayed engraftment remains a major hurdle after cord blood (CB) transplantation. It may be due, at least in part, to low fucosylation of cell surface molecules important for homing to the bone marrow microenvironment. Because fucosylation of specific cell surface ligands is required before effective interaction with selectins expressed by the bone marrow microvasculature can occur, a simple 30-minute ex vivo incubation of CB hematopoietic progenitor cells with fucosyltransferase-VI and its substrate (GDP-fucose) was performed to increase levels of fucosylation. The physiologic impact of CB hematopoietic progenitor cell hypofucosylation was investigated in vivo in NOD-SCID interleukin (IL)-2Rγ(null) (NSG) mice. By isolating fucosylated and nonfucosylated CD34(+) cells from CB, we showed that only fucosylated CD34(+) cells are responsible for engraftment in NSG mice. In addition, because the proportion of CD34(+) cells that are fucosylated in CB is significantly less than in bone marrow and peripheral blood, we hypothesize that these combined observations might explain, at least in part, the delayed engraftment observed after CB transplantation. Because engraftment appears to be correlated with the fucosylation of CD34(+) cells, we hypothesized that increasing the proportion of CD34(+) cells that are fucosylated would improve CB engraftment. Ex vivo treatment with fucosyltransferase-VI significantly increases the levels of CD34(+) fucosylation and, as hypothesized, this was associated with improved engraftment. Ex vivo fucosylation did not alter the biodistribution of engrafting cells or pattern of long-term, multilineage, multi-tissue engraftment. We propose that ex vivo fucosylation will similarly improve the rate and magnitude of engraftment for CB transplant recipients in a clinical setting.
Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. snrobins@mdanderson.org
Simon N
SN
Robinson
Paul J
PJ
Simmons
Michael W
MW
Thomas
Nathalie
N
Brouard
Jeannie A
JA
Javni
Suprita
S
Trilok
Jae-Seung
JS
Shim
Hong
H
Yang
David
D
Steiner
William K
WK
Decker
Dongxia
D
Xing
Leonard D
LD
Shultz
Barbara
B
Savoldo
Gianpietro
G
Dotti
Catherine M
CM
Bollard
Leonard
L
Miller
Richard E
RE
Champlin
Elizabeth J
EJ
Shpall
Patrick A
PA
Zweidler-McKay
D000818:Animals; D018952:Antigens, CD34 / Q000276:immunology; D001854:Bone Marrow Cells / Q000378:metabolism; D019070:Cell Lineage; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology / Q000637:transplantation*; D005434:Flow Cytometry; D005643:Fucose / Q000378:metabolism*; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D014183:Transplantation, Heterologous
D018952:Antigens, CD34; D053631:Interleukin Receptor Common gamma Subunit; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D005643:Fucose