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Blood, Vol. 93 No. 5 (March 1), 1999:
pp. 1557-1566
Organ-Selective Homing Defines Engraftment Kinetics of Murine
Hematopoietic Stem Cells and Is Compromised by Ex Vivo Expansion
Stephen J. Szilvassy,
Michael J. Bass,
Gary Van Zant, and
Barry Grimes
From the Blood and Marrow Transplant Program, and the Division of
Hematology/Oncology, Lucille P. Markey Cancer Center, University of
Kentucky, Lexington, KY.
Hematopoietic reconstitution of ablated recipients requires that
intravenously (IV) transplanted stem and progenitor cells "home"
to organs that support their proliferation and differentiation. To
examine the possible relationship between homing properties and
subsequent engraftment potential, murine bone marrow (BM) cells were
labeled with fluorescent PKH26 dye and injected into lethally
irradiated hosts. PKH26+ cells homing to marrow or spleen
were then isolated by fluorescence-activated cell sorting and assayed
for in vitro colony-forming cells (CFCs). Progenitors accumulated
rapidly in the spleen, but declined to only 6% of input numbers after
24 hours. Although egress from this organ was accompanied by a
simultaneous accumulation of CFCs in the BM (plateauing at 6% to 8%
of input after 3 hours), spleen cells remained enriched in donor CFCs
compared with marrow during this time. To determine whether this
differential homing of clonogenic cells to the marrow and spleen
influenced their contribution to short-term or long-term hematopoiesis
in vivo, PKH26+ cells were sorted from each organ 3 hours
after transplantation and injected into lethally irradiated Ly-5
congenic mice. Cells that had homed initially to the spleen regenerated
circulating leukocytes (20% of normal counts) approximately 2 weeks
faster than cells that had homed to the marrow, or PKH26-labeled cells that had not been selected by a prior homing step. Both primary (17 weeks) and secondary (10 weeks) recipients of "spleen-homed" cells also contained approximately 50% higher numbers of CFCs per
femur than recipients of "BM-homed" cells. To examine whether progenitor homing was altered upon ex vivo expansion, highly enriched Sca-1+c-kit+Lin
cells were cultured for 9 days in serum-free medium containing interleukin (IL)-6, IL-11, granulocyte colony-stimulating factor, stem
cell factor, flk-2/flt3 ligand, and thrombopoietin. Expanded cells were
then stained with PKH26 and assayed as above. Strikingly, CFCs
generated in vitro exhibited a 10-fold reduction in homing capacity
compared with fresh progenitors. These studies demonstrate that
clonogenic cells with differential homing properties contribute variably to early and late hematopoiesis in vivo. The dramatic decline
in the homing capacity of progenitors generated in vitro underscores
critical qualitative changes that may compromise their biologic
function and potential clinical utility, despite their efficient
numerical expansion.
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