Release from quiescence of primitive human hematopoietic stem/progenitor cells by blocking their cell-surface TGF-β type II receptor in a short-term in vitro assay

Genetic alterations of the signaling cascade of transforming growth factor-beta (TGF-beta) are often associated with neoplastic transformation of primitive cells. This demonstrates the key role for this pleiotropic factor in the control of quiescence and cell proliferation in vivo. In the high proliferative potential-quiescent cell (HPP-Q) in vitro assay, the use of TGF-beta 1 blocking antibodies (anti-TGF-beta 1) allows the detection within two to three weeks of primitive hematopoietic cells called HPP-Q, which otherwise would not grow. However, the possibility of triggering cell proliferation by blocking the cell-surface TGF-beta receptors has not been investigated until now, We have tested here the efficiency of a blocking antibody against TGF-beta RII (anti-TGF-beta RII) on CD34(+)CD38(-) hematopoietic cells, a subpopulation enriched in primitive stem/progenitor cells, and compared its effect with that of anti-TGF-beta 1, About twice as many HPP colony-forming cells were detected in the presence of anti-TGF-beta 1 or anti-TGF-beta RII, compared to the control (p < 0.02). Moreover, anti-TGF-beta RII was as efficient as anti-TGF-beta 1 for activating multipotent HPP-granulocyte erythroid macrophage megakaryocyte and HPP-Mix, bipotent HPP-granulocyte-macrophage (GM) and unipotent HPP-Q, HPP-M and HPP-BFU-E, We therefore propose the use of anti-TGF-beta RII: to release primitive cells from quiescence in the HPP-Q assay, This strategy could be extended to nonhematopoietic tissues, as TGF-beta 1 may be a pleiotropic regulator of somatic stem cell quiescence.