Distinct role of gp130 activation in promoting self-renewal divisions by mitogenically stimulated murine hematopoietic stem cells

Abstract

Previous studies have demonstrated hematopoietic stem cell amplification in vitro after the activation of three cell-surface receptors: flt3͞flk2, c-kit, and gp130. We now show flt3-ligand and Steel factor alone will stimulate >85% of c-kit ؉ Sca-1 ؉ lin ؊ adult mouse bone marrow cells to proliferate in single-cell serum-free cultures, but concomitant retention of their stem cell activity requires additional exposure to a ligand that will activate gp130. Moreover, this response is restricted to a narrow range of gp130-activating ligand concentrations, above and below which hematopoietic stem cell activity is lost. These findings indicate a unique contribution of gp130 signaling to the maintenance of hematopoietic stem cell function when these cells are stimulated to divide with additional differential effects dictated by the intensity of gp130 activation.IL-6 ͉ serum-free culture

Enforced expression of cyclin D2 enhances the proliferative potential of myeloid progenitors, accelerates in vivo myeloid reconstitution, and promotes rescue of mice from lethal myeloablation

“…Because combinations of 3 to 5 cytokines have been demonstrated to optimally promote proliferation of hematopoietic stem and progenitor cells, 8,30 it was of particular interest that overexpression of cyclin D2 was able to further enhance proliferation of transduced progenitors stimulated simultaneously by high concentrations of 5 cytokines. This suggests that cyclin D2 can promote hematopoietic progenitor proliferation beyond what can be obtained by known cytokines.…”

Basic Fibroblast Growth Factor Supports Undifferentiated Human Embryonic Stem Cell Growth Without Conditioned Medium

“…For instance, factors in the IL-6 family maintain the pluripotentiality of mouse embryonic stem (ES) cells through activation of the STAT3 pathway [22][23][24][25][26][27]. In addition, growth of human primordial germ cells requires LIF, SCF, and bFGF [28], whereas SCF, FLT3L, TPO, and IL-6 synergize with each other to promote expansion of hematopoietic progenitors [29][30][31][32][33][34][35][36][37]. In this report, we demonstrate that hESCs can be maintained in bFGF or bFGF in combination with other growth factors in a serum replacement nonconditioned medium (SR medium).…”

Unique effects of Stat3 on the early phase of hematopoietic stem cell regeneration

“…However, a rapid and extensive net expansion of HSCs can be reinitiated in vivo following damage to the hematopoietic system. 6 Accumulating evidence points to the involvement of both extrinsic cues (eg, Steel factor, factors that activate gp130, 7 notch ligands, 8 and Wnt 9 ) as well as intrinsic regulators (eg, p21 cip1/waf1 , 10 Bmi-1, 11,12 and HoxB4 [13][14][15] ) in controlling HSC self-renewal responses following their mitogenic activation in vitro or in vivo. Relatively little, however, is known about the signaling intermediates that direct or can modulate changes in HSC self-renewal when these cells are stimulated to proliferate in vivo.…”