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Blood, Vol. 94 No. 2 (July 15), 1999:
pp. 483-495
All-Trans Retinoic Acid Delays the Differentiation of Primitive
Hematopoietic Precursors
(lin c-kit+Sca-1+)
While Enhancing the Terminal Maturation of Committed
Granulocyte/Monocyte Progenitors
Louise E. Purton,
Irwin D. Bernstein, and
Steven J. Collins
From the Clinical Research and Molecular Medicine Divisions, Fred
Hutchinson Cancer Research Center, Seattle, WA; and The Department of
Pediatrics, The University of Washington, Seattle, WA.
All-trans retinoic acid (ATRA) is a potent inducer of terminal
differentiation of malignant promyelocytes, but its effects on more
primitive hematopoietic progenitors and stem cells are less clear. In
this study, we investigated the effect of ATRA on highly enriched
murine hematopoietic precursor cells
(lin c-kit+Sca-1+)
grown in liquid suspension culture for 28 days. ATRA initially slowed
the growth of these hematopoietic precursors but prolonged and markedly
enhanced their colony-forming cell production compared with the
hematopoietic precursors cultured in its absence. At 7 and 14 days of
culture, a substantially greater percentage of cells cultured with ATRA
did not express lineage-associated antigens (55.4% at day 7 and 68.6%
at day 14) and retained expression of Sca-1 (44.7% at day 7 and 79.9%
at day 14) compared with cells grown in its absence (lin
cells: 31.5% at day 7 and 4% at day 14; Sca-1+: 10.4%
at day 7 and 0.7% at day 14). Moreover, a marked inhibition of
granulocyte production was observed in cultures continuously incubated
with ATRA. Significantly, ATRA markedly prolonged and enhanced the
production of transplantable colony-forming unit-spleen (CFU-S) during
14 days of liquid suspension culture. In contrast with its effects on
primitive
linc-kit+Sca-1+
hematopoietic precursors, ATRA did not exert the same effects on the
more committed
linc-kit+Sca-1
progenitor cells. Moreover, the late addition of ATRA (7 days post-culture initiation) to cultures of primitive hematopoietic precursors resulted in a marked decrease in colony-forming cell production in these cultures, which was associated with enhanced granulocyte differentiation. These observations indicate that ATRA has
different effects on hematopoietic cells depending on their
maturational state, preventing and/or delaying the differentiation of
primitive hematopoietic precursors while enhancing the terminal differentiation of committed granulocyte/monocyte progenitors.
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