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Transplantation of Human Umbilical Cord Blood Cells in
Macrophage-Depleted SCID Mice: Evidence for Accessory Cell Involvement
in Expansion of Immature CD34+CD38
Cells
Monique M.A. Verstegen,
Paula B. van Hennik,
Wim Terpstra,
Cor van
den Bos,
Jenne J. Wielenga,
Nico van Rooijen,
Rob E. Ploemacher,
Gerard Wagemaker, and
Albertus W. Wognum
From the Institute of Hematology, Erasmus University Rotterdam,
Rotterdam, The Netherlands; and the Department of Biochemistry, Free
University Amsterdam, Amsterdam, The Netherlands.
In vivo expansion and multilineage outgrowth of human immature
hematopoietic cell subsets from umbilical cord blood (UCB) were studied
by transplantation into hereditary immunodeficient (SCID) mice. The
mice were preconditioned with Cl2MDP-liposomes to deplete
macrophages and 3.5 Gy total body irradiation (TBI). As measured by
immunophenotyping, this procedure resulted in high levels of human
CD45+ cells in SCID mouse bone marrow (BM) 5 weeks after
transplantation, similar to the levels of human cells observed in
NOD/SCID mice preconditioned with TBI. Grafts containing approximately
107 unfractionated cells, approximately 105
purified CD34+ cells, or 5 × 103 purified
CD34+CD38 cells yielded equivalent numbers
of human CD45+ cells in the SCID mouse BM, which
contained human CD34+ cells, monocytes, granulocytes,
erythroid cells, and B lymphocytes at different stages of maturation.
Low numbers of human GpA+ erythroid cells and
CD41+ platelets were observed in the peripheral blood of
engrafted mice. CD34+CD38+ cells (5 × 104/mouse) failed to engraft, whereas
CD34 cells (107/mouse) displayed only low
levels of chimerism, mainly due to mature T lymphocytes.
Transplantation of graded numbers of UCB cells resulted in a
proportional increase of the percentages of CD45+ and
CD34+ cells produced in SCID mouse BM. In contrast, the
number of immature, CD34+CD38 cells
produced in vivo showed a second-order relation to CD34+
graft size, and mice engrafted with purified
CD34+CD38 grafts produced 10-fold fewer
CD34+ cells without detectable
CD34+CD38 cells than mice transplanted
with equivalent numbers of unfractionated or purified
CD34+ cells. These results indicate that SCID
repopulating CD34+CD38 cells require
CD34+CD38+ accessory cell support for
survival and expansion of immature cells, but not for production of
mature multilineage progeny in SCID mouse BM. These accessory cells are
present in the purified, nonrepopulating
CD34+CD38+ subset as was directly proven by
the ability of this fraction to restore the maintenance and expansion
of immature CD34+CD38 cells in vivo when
cotransplanted with purified CD34+CD38
grafts. The possibility to distinguish between maintenance and outgrowth of immature repopulating cells in SCID mice will facilitate further studies on the regulatory functions of accessory cells, growth
factors, and other stimuli. Such information will be essential to
design efficient stem cell expansion procedures for clinical use.
Blood, Vol. 91 No. 6 (March 15), 1998:
pp. 1966-1976
© 1998 by The American Society of Hematology.
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