TY - JOUR
T1 - Ex vivo fucosylation improves human cord blood engraftment in NOD-SCID IL-2Rγ null mice
AU - Robinson, Simon N.
AU - Simmons, Paul J.
AU - Thomas, Michael W.
AU - Brouard, Nathalie
AU - Javni, Jeannie A.
AU - Trilok, Suprita
AU - Shim, Jae Seung
AU - Yang, Hong
AU - Steiner, David
AU - Decker, William K.
AU - Xing, Dongxia
AU - Shultz, Leonard D.
AU - Savoldo, Barbara
AU - Dotti, Gianpietro
AU - Bollard, Catherine M.
AU - Miller, Leonard
AU - Champlin, Richard E.
AU - Shpall, Elizabeth J.
AU - Zweidler-McKay, Patrick A.
N1 - Funding Information:
This work was supported in part by Cancer Prevention and Research Institute of Texas (CPRIT) grant # RP100469 and National Institutes of Health grant # RO1-CA061508-15 (E.J.S. and P.J.S.). The authors gratefully acknowledge the provision of FT-VI by America Stem Cell, Inc., Carlsbad, CA and the assistance of Ms. Junjun Lu and Ms. Tuong-Van Nguyen (Department of Stem Cell Transplantation and Cellular Therapy) and Ms. Wendy Fang (Division of Pediatrics), University of Texas MD Anderson Cancer Center, Houston, TX.
PY - 2012/6
Y1 - 2012/6
N2 - 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.
AB - 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.
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U2 - 10.1016/j.exphem.2012.01.015
DO - 10.1016/j.exphem.2012.01.015
M3 - Article
C2 - 22306295
AN - SCOPUS:84862777323
SN - 0301-472X
VL - 40
SP - 445
EP - 456
JO - Experimental Hematology
JF - Experimental Hematology
IS - 6
ER -