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Blood, 15 December 2001, Vol. 98, No. 13, pp. 3643-3649
HEMATOPOIESIS
Transforming growth factor  1 mediates cell-cycle arrest of
primitive hematopoietic cells independent of p21Cip1/Waf1
or p27Kip1
Tao Cheng,
Hongmei Shen,
Neil Rodrigues,
Sebastian Stier, and
David T. Scadden
From the MGH Cancer Center and AIDS Research Center,
Massachusetts General Hospital, Harvard Medical School, Boston, MA, and
Radiation Oncology, University of Pittsburgh Cancer Institute,
Pittsburgh, PA.
The regulation of stem cell proliferation is a poorly understood
process balancing rapid, massive blood cell production in times of
stress with maintenance of a multipotent stem cell pool over decades of
life. Transforming growth factor  1 (TGF-1) has pleiotropic
effects on hematopoietic cells, including the inhibition of primitive
cell proliferation. It was recently demonstrated that the
cyclin-dependent kinase inhibitors, p21Cip1/Waf1 (p21) and
p27Kip1 (p27), can inhibit the proliferation of
hematopoietic stem cells and progenitor cells, respectively. The
relation of TGF-1 stimulation to p21 and p27 was examined using a
fine-mapping approach to gene expression in individual cells. Abundant
TGF-1 expression and p21 expression were documented in quiescent,
cytokine-resistant hematopoietic stem cells and in terminally
differentiated mature blood cells, but not in proliferating progenitor
cell populations. TGF-1 receptor (TR II) was expressed
ubiquitously without apparent modulation. Cell- cycle-synchronized 32D
cells exposed to TGF-1 demonstrated a marked antiproliferative
effect of TGF-1, yet neither the level of p21 mRNA nor the protein
level of either p21 or p27 was altered. To corroborate these
observations in primary cells, bone marrow mononuclear cells derived
from mice engineered to be deficient in p21 or p27 were assessed.
Progenitor and primitive cell function was inhibited by TGF-1
equivalently in  / and +/+ littermate controls. These data indicate
that TGF-1 exerts its inhibition on cell cycling independent of p21
and p27 in hematopoietic cells. TGF-1 and p21 or p27 participate in
independent pathways of stem cell regulation, suggesting that targeting
each may provide complementary strategies for enhancing stem or
progenitor cell expansion and gene transduction.
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