p21(cip1) mRNA is controlled by endogenous transforming growth factor-beta1 in quiescent human hematopoietic stem/progenitor cells

Transforming growth factor-beta 1 (TCF-beta 1) has been described as an eff icient 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 e ffect of TGF-beta 1 in maintaining the reversible quiescence of the more pr imitive hematopoietic stem cell compartment. HPP-Q cells are primitive quie scent stem/progenitor cells on which TGF-beta 1 has downmodulated the cytok ine receptors. These cells can be released from quiescence by neutralizatio n of autocrine or endogenous TGF-beta 1 with a TGF-beta 1 blocking antibody or a TGF-beta 1 antisense oligonucleotide. In nonhematopoietic systems, TG F-beta 1 cooperates with the cyclin-dependent kinase inhibitor, p21(cip1), to induce cell cycle arrest. We therefore analyzed whether endogenous TGF-b eta 1 controls the expression of the p21(cip1) in the CD34(+) undiferentiat ed cells using a sensitive in situ hybridization method. We observed that a ddition of anti-TGF-beta 1 is followed by a rapid decrease in the level of p21(cip1) mRNA whereas TGF-beta 1 enhances p21(cip1) mRNA expression concur rently with an inhibitory effect on progenitor cell proliferation. These re sults suggest the involvement of p21(cip1) in the cell cycle control of ear ly human hematopoietic quiescent stem/progenitors and not only in the diffe rentiation of more mature myeloid cells as previously described. The modula tion of p21(cip1) observed in response to TGF-beta 1 allows us to further p recise the working model of high proliferative potential-quiescent cells. J . Cell. Physiol. 184:80-85, 2000. (C) 2000 Wiley-Liss, Inc.