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Blood, Vol. 94 No. 1 (July 1), 1999:
pp. 106-113
Ex Vivo Expansion of Autologous Bone Marrow CD34+ Cells
With Porcine Microvascular Endothelial Cells Results in a Graft Capable
of Rescuing Lethally Irradiated Baboons
John E. Brandt,
Amelia M. Bartholomew,
Jeffrey D. Fortman,
Mary C. Nelson,
Edward Bruno,
Luci M. Chen,
Julius V. Turian,
Thomas A. Davis,
John P. Chute, and
Ronald Hoffman
From the Departments of Medicine and Radiation Oncology and the
Biological Resources Laboratory, University of Illinois at Chicago,
Chicago, IL; and the Naval Medical Research Institute, Bethesda, MD.
Hematopoietic stem cell (HSC) self-renewal in vitro has been
reported to result in a diminished proliferative capacity or acquisition of a homing defect that might compromise marrow
repopulation. Our group has demonstrated that human HSC expanded ex
vivo in the presence of porcine microvascular endothelial cells (PMVEC) retain the capacity to competitively repopulate human bone fragments implanted in severe combined immunodeficiency (SCID) mice. To further
test the marrow repopulating capacity of expanded stem cells, our
laboratory has established a myeloablative, fractionated total body
irradiation conditioning protocol for autologous marrow transplantation
in baboons. A control animal, which received no transplant, as well as
two animals, which received a suboptimal number of marrow mononuclear
cells, died 37, 43, and 59 days postirradiation, respectively.
Immunomagnetically selected CD34+ marrow cells from two
baboons were placed in PMVEC coculture with exogenous human cytokines.
After 10 days of expansion, the grafts represented a 14-fold to 22-fold
increase in cell number, a 4-fold to 5-fold expansion of
CD34+ cells, a 3-fold to 4-fold increase of
colony-forming unit-granulocyte-macrophage (CFU-GM), and a 12-fold to
17-fold increase of cobblestone area-forming cells (CAFC) over input.
Both baboons became transfusion independent by day 23 posttransplant
and achieved absolute neutrophil count (ANC) >500/µL by day 25 ± 1 and platelets >20,000/µL by day 29 ± 2. This
hematopoietic recovery was delayed in comparison to two animals that
received either a graft consisting of freshly isolated, unexpanded
CD34+ cells or 175 × 106/kg unfractionated
marrow mononuclear cells. Analysis of the proliferative status of cells
in PMVEC expansion cultures demonstrated that by 10 days, 99.8% of
CD34+ cells present in the cultures had undergone
cycling, and that the population of cells expressing a
CD34+ CD38 phenotype in the cultures was
also the result of active cell division. These data indicate that
isolated bone marrow CD34+ cells may undergo cell
division during ex vivo expansion in the presence of endothelial cells
to provide a graft capable of rescuing a myeloablated autologous host.
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