Developmentally regulated responsiveness to transforming growth factor-β is correlated with functional differences between human adult and fetal primitive hematopoietic progenitor cells

Abstract

Important functional differences exist between primitive CD34 ++ CD38 − hematopoietic progenitor cells derived from human fetal liver (FL) and adult bone marrow (ABM). FL progenitors are known to have higher proliferative capacities and lower cytokine requirements than their ABM counterparts. In this study, we isolated FL and ABM CD34 ++ CD38 − cells and used a two-stage culture system to investigate the effects of transforming growth factor-␤ (TGF-␤) and blocking anti-TGF-␤ antibodies (anti-TGF-␤) on these cells. First, we demonstrate that FL progenitors are significantly less sensitive to the inhibitory effects of TGF-␤ than ABM cells. Second, whereas ABM cells are significantly stimulated by anti-TGF-␤, only very limited effects are seen on FL cells. Third, we show that the effect of anti-TGF-␤ is mainly situated at the level of the initial cell cycles of very primitive progenitor cells with a high proliferation potential. Fourth, we demonstrate that blocking the effects of endogenous TGF-␤ reduces the growth factor requirements of ABM cells in order to proliferate and differentiate. Based on these data, we hypothesize that at least part of the functional differences that exist between adult and fetal stem cells can be accounted for by a developmental different responsiveness to TGF-␤.

Transient Disruption of Autocrine TGF-β Signaling Leads to Enhanced Survival and Proliferation Potential in Single Primitive Human Hemopoietic Progenitor Cells

“…This discrepancy may be due to the fact that different culture conditions induce the proliferation of divergent cell populations. It is also possible that the primitive hemopoietic progenitor cells from different sources may behave differently in response to TGF-␤ signaling and signaling of the other cytokines (40). The third possibility is that overexpression of T␤RIIDN blocks the signaling of all TGF-␤ isoforms, whereas the Ab or antisense oligonucleotide based approach may only block the signaling of one TGF-␤ isoform.…”

Transcription factor fusions in acute leukemia: variations on a theme

“…Early hematopoietic progenitors normally produce TGFb (Majka et al, 2001) that can act in an autocrine fashion (Batard et al, 2000), and neutralization of TGFb by monoclonal antibodies has been reported to recruit early progenitors into the cell cycle and induce them to dierentiate (Batard et al, 2000;Dao et al, 1998;Ducos et al, 2000;Pierelli et al, 2000;Weekx et al, 1999). Lineagerestricted progenitor cells are generally less responsive to growth inhibition by TGFb (Cashman et al, 1999, Sargiacomo et al, 1991, although some eects on apoptosis and dierentiation have been observed (Cashman et al, 1999;Dybedal et al, 1997).…”

In vitro evidence for differentiation resistance by distributed stem cells during deterministic asymmetric self-renewal

“…Cells in newly formed blastocysts are initially resistant to TGFß, but later in development, cells acquire TGFß sensitivity [31]. Moreover, the basis for TGFß-resistance by mouse embryonic stem cells is lack of RII receptors and corresponding absence of Smad 2 nuclear localization [33].…”

“…Fetal liver progenitor cells are also TGFß-resistant [33] and clusters of cells in primary fetal hepatocyte cultures have been shown resistant to differentiation by EGF and TGFß [27]. Thus, adifferentiation may be a general property of stem and progenitor cells, whether embryonic or adult; and reduced or absent RII expression may be the molecular basis.…”