Release from quiescence of primitive human hematopoietic stem/progenitor cells by blocking their cell-surface TGF-beta 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 prim itive cells. This demonstrates the key role for this pleiotropic factor in the control of quiescence and cell proliferation in vivo. In the high proli ferative potential-quiescent cell (HPP-Q) in vitro assay, the use of TGF-be ta 1 blocking antibodies (anti-TGF-beta 1) allows the detection within two to three weeks of primitive hematopoietic cells called HPP-Q, which otherwi se would not grow. However, the possibility of triggering cell proliferatio n by blocking the cell-surface TGF-beta receptors has not been investigated until now, We have tested here the efficiency of a blocking antibody again st TGF-beta RII (anti-TGF-beta RII) on CD34(+)CD38(-) hematopoietic cells, a subpopulation enriched in primitive stem/progenitor cells, and compared i ts effect with that of anti-TGF-beta 1, About twice as many HPP colony-form ing 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 a s efficient as anti-TGF-beta 1 for activating multipotent HPP-granulocyte e rythroid macrophage megakaryocyte and HPP-Mix, bipotent HPP-granulocyte-mac rophage (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 i n the HPP-Q assay, This strategy could be extended to nonhematopoietic tiss ues, as TGF-beta 1 may be a pleiotropic regulator of somatic stem cell quie scence.