p21cip1 mRNA is controlled by endogenous transforming growth factor-?1 in quiescent human hematopoietic stem/progenitor cells

Abstract

Transforming growth factor-beta1 (TGF-beta1) has been described as an efficient growth inhibitor that maintains the CD34(+) hematopoietic progenitor cells in quiescence. The concept of high proliferative potential-quiescent cells or HPP-Q cells has been introduced as a working model to study the effect of TGF-beta1 in maintaining the reversible quiescence of the more primitive hematopoietic stem cell compartment. HPP-Q cells are primitive quiescent stem/progenitor cells on which TGF-beta1 has downmodulated the cytokine receptors. These cells can be released from quiescence by neutralization of autocrine or endogenous TGF-beta1 with a TGF-beta1 blocking antibody or a TGF-beta1 antisense oligonucleotide. In nonhematopoietic systems, TGF-beta1 cooperates with the cyclin-dependent kinase inhibitor, p21(cip1), to induce cell cycle arrest. We therefore analyzed whether endogenous TGF-beta1 controls the expression of the p21(cip1) in the CD34(+) undifferentiated cells using a sensitive in situ hybridization method. We observed that addition of anti-TGF-beta1 is followed by a rapid decrease in the level of p21(cip1) mRNA whereas TGF-beta1 enhances p21(cip1) mRNA expression concurrently with an inhibitory effect on progenitor cell proliferation. These results suggest the involvement of p21(cip1) in the cell cycle control of early human hematopoietic quiescent stem/progenitors and not only in the differentiation of more mature myeloid cells as previously described. The modulation of p21(cip1) observed in response to TGF-beta1 allows us to further precise the working model of high proliferative potential-quiescent cells.

A sub-population of high proliferative potential-quiescent human mesenchymal stem cells is under the reversible control of interferon α/β

“…29 Thus, the use of antisense oligonucleotides has revealed that hHSC quiescence is mediated in part through an autocrine loop involving TGFb1. [30][31][32][33] Similar results have been obtained using either antibodies against TGF-b 25,31,34 or antibodies against the TGF-b cell-surface type II receptor (anti-TbR-II). 35 The aim of the present study was to address the question of a possible involvement of type I interferons (IFN), as negative regulators of the cell cycle of human bone marrow-derived mesenchymal precursor cells, as IFNa has been described as a potent inhibitor of marrow stromal cells.…”

Cell cycle regulators and hematopoiesis

“…In CD34+lin7 cells, TGF ± b1 is antiproliferative (Dao et al, 1998;Fortunel et al, 2000a,b) and anti-TGF-b1 antibody has been shown to increase the recruitment of cells into cycle. TGF-b1 has been shown to increase p21 transcription in CD34+ cells (Ducos et al, 2000) and in nonhematopoietic cells (Datto et al, 1995). However, neutralization of TGF-b1 alone has not been su cient to promote cycling of CD34+ cells selected with 4-HC or 5-FU for cytokine resistance (Steinman, unpublished observations, and Dao et al, (1998)).…”

Signal transduction pathways that contribute to myeloid differentiation

“…Treatment with TGFb1 blocking antibodies or TGFb1 antisense oligonucleotides releases the stem cells from their quiescent state to an active cycling state allowing subsequent expansion of this population to occur. 251 The differentiation of myeloid progenitors into granulocyte or monocytes, on the other hand, is enhanced by TGFb. [252][253][254] Several studies have demonstrated that the negative regulation of hematopoiesis by TGFb is mediated by the Smad proteins.…”