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Blood, Vol. 93 No. 3 (February 1), 1999:
pp. 1097-1105
Delayed Engraftment of Nonobese Diabetic/Severe Combined
Immunodeficient Mice Transplanted With Ex Vivo-Expanded Human
CD34+ Cord Blood Cells
G. Güenechea,
J.C. Segovia,
B. Albella,
M. Lamana,
M. Ramírez,
C. Regidor,
M.N. Fernández, and
J.A. Bueren
From the U. Biología Molecular y Celular, CIEMAT and Servicio
de Hematología, H. Puerta de Hierro, Madrid, Spain.
The ex vivo expansion of hematopoietic progenitors is a promising
approach for accelerating the engraftment of recipients, particularly
when cord blood (CB) is used as a source of hematopoietic graft. With
the aim of defining the in vivo repopulating properties of ex
vivo-expanded CB cells, purified CD34+ cells were
subjected to ex vivo expansion, and equivalent proportions of fresh and
ex vivo-expanded samples were transplanted into irradiated nonobese
diabetic (NOD)/severe combined immunodeficient (SCID) mice. At periodic
intervals after transplantation, femoral bone marrow (BM) samples were
obtained from NOD/SCID recipients and the kinetics of engraftment
evaluated individually. The transplantation of fresh
CD34+ cells generated a dose-dependent engraftment of
recipients, which was evident in all of the posttransplantation times
analyzed (15 to 120 days). When compared with fresh CB, samples
stimulated for 6 days with interleukin-3 (IL-3)/IL-6/stem cell factor
(SCF) contained increased numbers of hematopoietic progenitors (20-fold increase in colony-forming unit granulocyte-macrophage [CFU-GM]). However, a significant impairment in the short-term repopulation of
recipients was associated with the transplantation of the ex vivo-expanded versus the fresh CB cells (CD45+
repopulation in NOD/SCIDs BM: 3.7% ± 1.2% v 26.2% ± 5.9%, respectively, at 20 days posttransplantation; P < .005). An impaired short-term engraftment was also observed in mice
transplanted with CB cells incubated with IL-11/SCF/FLT-3
ligand (3.5% ± 1.7% of CD45+ cells in
femoral BM at 20 days posttransplantation). In contrast to these data,
a similar repopulation with the fresh and the ex vivo-expanded cells
was observed at later stages posttransplantation. At 120 days, the
repopulation of CD45+ and
CD45+/CD34+ cells in the femoral BM of
recipients ranged between 67.2% to 81.1% and 8.6% to 12.6%,
respectively, and no significant differences of engraftment between
recipients transplanted with fresh and the ex vivo-expanded samples
were found. The analysis of the engrafted CD45+ cells
showed that both the fresh and the in vitro-incubated samples were
capable of lymphomyeloid reconstitution. Our results suggest that
although the ex vivo expansion of CB cells preserves the long-term
repopulating ability of the sample, an unexpected delay of engraftment
is associated with the transplantation of these manipulated cells.
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