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Prepublished online as a Blood First Edition Paper on August 22, 2002; DOI 10.1182/blood-2002-02-0486.
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Blood, 1 January 2003, Vol. 101, No. 1, pp. 45-51
CHEMOKINES
Heterologous cells cooperate to augment stem cell migration,
homing, and engraftment
Gregor B. Adams,
Karissa T. Chabner,
Russell B. Foxall,
Kathryn W. Weibrecht,
Neil P. Rodrigues,
David Dombkowski,
Robert Fallon,
Mark C. Poznansky, and
David T. Scadden
From the Partners AIDS Research Center and MGH Cancer
Center, Harvard Medical School, Massachusetts General Hospital, Boston;
and Indiana University Cancer Research Institute, Indiana University
School of Medicine, Indianapolis.
T-lymphocyte depletion of bone marrow grafts compromises
engraftment, suggesting a facilitating mechanism provided by the T
cells that has been shown to associate with CD8+ but not
CD4+ T cells. Explanations for this phenomenon have focused
on immune targeting of residual host cells or cytokine production. We
provide evidence for an alternative mechanism based on cooperative
effects on cell motility. We observed that engraftment of
CD34+ cells in a 2-microglobulin-deficient
nonobese diabetic/severe combined immunodeficiency
( 2m / NOD/SCID) mouse model paralleled
clinical observations in humans, with an enhancing effect noted from
the addition of CD8+ cells but not CD4+ cells.
This correlated with CD8+ augmentation of CD34+
cell homing to the bone marrow in vivo and CD8+
cell-associated increases of CD34+ cell transmigration
through a bone marrow endothelial cell line in vitro. The cooperative
interaction was not sensitive to brefeldin A inhibition of protein
secretion. However, cytochalasin D-induced inhibition of
CD8+ cytoskeletal rearrangements abrogated
CD34+ transendothelial migration and impaired
CD34+ cell homing in vivo. CD8+ cells did not
migrate in tandem with CD34+ cells or alter endothelial
barrier integrity; rather, they affected phosphotyrosine-mediated
signaling in CD34+ cells in response to the chemokine
stromal derived factor-1 (SDF-1 ). These data demonstrate
cell-cell cooperativity between different cell types in mediating
chemotactic events and provide one potential explanation for the
clinically observed effect of CD8+ cells on bone marrow
transplantation. This modification of cell migration by neighboring
cells provides broad possibilities for combinatorial effects between
cells of different types to influence cell localization.

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