Cytokine in Normal/Neoplastic Hematopoietic Cell Growth

我们和其他人已经表明，为了启动和维持原始祖细胞的生长和分化，需要多种细胞因子刺激（协同作用）。最近，我们发现，这种合作也发生在细胞生长的负调节因子之间，并且原始祖细胞增殖的能力取决于细胞接收的正信号和负信号的平衡。转化生长因子β（TGF？）直接和可逆地抑制具有骨髓再生能力的造血干细胞（LT-HSC）。此外，短期孵育与抗体和反义TGF？刺激这些干细胞的自我更新潜力。转化生长因子对许多细胞因子受体的细胞表面表达具有抑制作用，所述细胞因子受体与其对细胞生长的作用直接相关。例如，干细胞因子受体（c-kit）表达受TGF β下调，部分通过影响c-kit mRNA的稳定性。这些结果表明LT-HSC对c-kit表达有负调控作用。事实上，我们能够表征缺乏c-kit表达的新型LT-HSC，并且在骨髓细胞发育中，该细胞成熟为c-kit+ LT-HSC。此外，TGF？通过涉及转录因子和细胞周期调节蛋白的调节的细胞内机制阻止S期细胞周期进展。在体内的结果表明，TGF？对5-FU的致死性造血毒性和DXR的非造血毒性均有保护作用。这些发现表明，造血的负调节剂可以成功地用于全身介导体内化学保护。许多实验室的先前结果也表明，TGF？在骨髓移植（BMT）之前处理供体细胞可以通过阻断免疫反应性而具有有益效果。我们能够显示抑制移植物抗宿主病（GVHD）后，异基因骨髓移植通过TGF？中介机制。用TGF？处理供体CD 4 T细胞IL-10使供体T细胞反应低下，促进GVHD的能力降低。在许多情况下，终末分化或抗癌药物治疗后的生长抑制导致细胞凋亡（程序性细胞死亡）。

We and others have shown that to initiate and maintain the growth and differentiation of primitive progenitor cells, multiple cytokine stimulation (synergy) is required. More recently, we showed that such cooperation also occurs between negative regulators of cell growth, and that the ability of primitive progenitors to proliferate depends on the balance of positive and negative signals the cell receives. Transforming growth factor beta (TGF?) directly and reversibly inhibits hematopoietic stem cells with marrow repopulating ability (LT-HSC). Also, short-term incubation with antibody and antisense to TGF? stimulates the self-renewal potential of these stem cells. TGF? has inhibitory effects on the cell surface expression of many cytokine receptors that directly correlates with its effect on cell growth. For example, stem cell factor receptor (c-kit) expression is downregulated by TGF?, in part by affecting c-kit mRNA stability. These results indicated that c-kit expression couldbe negatively regulated on LT-HSC. Indeed, we were able to characterize a novel LT-HSC lacking c-kit expression and that in bone marrow cell development, this cell matures into a c-kit+ LT-HSC. Also, TGF? prevents S phase cell-cycle progression through an intracellular mechanism involving regulation of transcription factors and cell-cycle regulatory proteins. In vivo results demonstrated that TGF? can protect mice from both the lethal hematopoietic toxicity of 5-FU, as well as the nonhematopoiesis toxicity of DXR. These findings show that a negative regulator of hematopoiesis can be successfully used systemically to mediate chemoprotection in vivo. Previous results from many labs also indicated that TGF? treatment of donor cells before bone marrow transplantation (BMT) could have a beneficial effect by blocking the immune reactivity. We were able to show suppression of graft vs host disease (GVHD) after allogeneic BMT through a TGF? mediated mechanism. Treatment of donor CD4 T-cells with TGF? and IL-10 made the donor T-cells hyporesponsive and less able to promote GVHD. In many instances, growth inhibition following terminal differentiation or anti-cancer drug treatment results in apoptosis (programmed cell death).