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Signaling Leads to Enhanced Survival and Proliferation Potential in Single Primitive Human Hemopoietic Progenitor Cells1
Departments of
*
Molecular Medicine and
Stem Cell Biology, Lund University, Lund, Sweden; and
Division of Cellular Biochemistry, Netherlands Cancer Institute, Amsterdam, The Netherlands
Hemopoietic stem cells (HSCs) are maintained at relative quiescence
by the balance between the positive and negative regulatory factors
that stimulate or inhibit their proliferation. Blocking the action of
negative regulatory factors may provide a new approach for inducing
HSCs into proliferation. A variety of studies have suggested that
TGF-
negatively regulates cell cycle progression of HSCs. In this
study, a dominant negatively acting mutant of TGF- type II receptor
(TRIIDN) was transiently expressed in HSCs by using adenoviral
vector-mediated gene delivery, such that the effects of disrupting the
autocrine TGF- signaling in HSCs can be directly examined at a
single cell level. Adenoviral vectors allowing the expression of
TRIIDN and green fluorescence protein in the same
CD34+CD38-Lin- cells were
constructed. Overexpression of TRIIDN specifically disrupted
TGF--mediated signaling. Autocrine TGF- signaling in
CD34+CD38-Lin- cells was studied
in single cell assays under serum-free conditions. Transient blockage
of autocrine TGF- signaling in
CD34+CD38-Lin- cells enhanced
their survival. Furthermore, the overall proliferation potential and
proliferation kinetics in these cells were significantly enhanced
compared with the CD34+CD38-Lin-
cells expressing green fluorescence protein alone. Therefore, we have
successfully blocked the autocrine TGF--negative regulatory loop of
primitive hemopoietic progenitor cells.
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