Cytokine in Normal/Neoplastic Hematopoietic Cell Growth

我们和其他人已经证明，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)。最近，我们发现，这种合作也发生在细胞生长的负面调控因素之间，原始祖细胞的增殖能力取决于细胞接收到的积极和消极信号的平衡。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)。另外，短期孵育抗转化生长因子抗体和反义转化生长因子？刺激这些干细胞的自我更新能力。转化生长因子？对细胞表面许多细胞因子受体的表达具有抑制作用，这与其对细胞生长的影响直接相关。例如，干细胞因子受体(c-kit)的表达被转化生长因子β下调，部分是通过影响c-kit mRNA的稳定性。这些结果表明，c-kit的表达对LT-HSC具有负性调节作用。事实上，我们能够鉴定出一种新型的缺乏c-kit表达的LT-HSC，并且在骨髓细胞发育过程中，这种细胞成熟为c-kit+LT-HSC。还有，转化生长因子？通过调节转录因子和细胞周期调节蛋白的细胞内机制，阻止S期细胞周期进展。体内实验结果表明，转化生长因子？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，一种负的造血调节因子可以成功地在体内系统地介导化学保护。此前多个实验室的研究结果也表明，转化生长因子？在骨髓移植(BMT)前对供体细胞进行处理可能会通过阻断免疫反应而产生有益的效果。我们能够通过转化生长因子？显示异基因骨髓移植后移植物抗宿主病(GVHD)的抑制。中介机制。用转化生长因子治疗供者CD4T细胞？IL-10使供者T细胞反应迟钝，不能促进移植物抗宿主病。在许多情况下，终末分化或抗癌药物治疗后的生长抑制会导致细胞凋亡(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).