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Flt3 ligand induces proliferation of quiescent human bone marrow CD34+CD38-
cells and maintains progenitor cells in vitro
AJ Shah, EM Smogorzewska, C Hannum and GM Crooks
Division of Hematology-Oncology, Childrens Hospital Los Angeles, CA 90027,
USA.
Flt3 is a class III tyrosine kinase receptor expressed on primitive human
and murine hematopoietic progenitor cells (HPC). In previous studies using
stroma-free short term assays, Flt3 ligand (FL) has been shown to induce
proliferation of HPC at proportions similar to or less than c-kit ligand
(steel factor, SF). Using long term stromal cocultivation assays, we
studied the effects of FL on proliferation and differentiation of a highly
primitive and cytokine nonresponsive subpopulation of human HPC, CD34+cd38-
cells. Cell Proliferation was significantly greater with FL than with SF,
when used individually or in combinations with interleukin-3 (IL-3) and/or
IL-6. The effect of FL was greater on bone marrow (BM) CD34+CD38- cells
than the more cytokine responsive cord blood CD34+CD38- cells. Little or no
effect was seen with FL on more mature CD34+CD38+ cells from either BM or
cord blood. The frequency of colony-forming units (CFU) and high
proliferative potential-colony forming cells (HPP-CFC) during early culture
( < or = 30 days) was increased by both SF and FL to similar levels.
However, in the LTC-IC period (35 to 60 days) and extended long-term
culture initiating cell (ELTC-IC) period ( > 60 days), the frequency of
CFU and HPP-CFC was significantly greater in cultures containing FL than
those without FL (P < .0025). Fluorescence-activated cell sorter
analysis of cultures after 21 days showed a significantly higher percentage
of cells remained CD34+ in the combination of FL, IL-3, IL-6, and SF
(F/3/6/S) than in 3/6/S (0.78% +/- 0.52% v 0.21% +/- 0.29% respectively,
mean +/- SD). Cloning efficiency of BM CD34+CD38- cells was significantly
increased by the addition of FL to the combination of 3/6/S (mean 11.7% v
0.5%, P < .0001). These data show that FL is able to induce
proliferation of CD34+CD38-cells that are nonresponsive to other early
acting cytokines and to improve the maintenance of progenitors in vitro.
Volume 87,
Issue 9,
pp. 3563-3570,
05/01/1996
Copyright © 1996 by The American Society of Hematology
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