Cytokine Regulation of Normal and 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，并且原始祖细胞的增殖能力取决于细胞接收的正、负信号的平衡。转化生长因子β (tgfβ)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，与抗体和TGFbeta的反义抗体短期孵育可以刺激这些干细胞的自我更新潜力。tgf β对许多细胞因子受体的细胞表面表达有抑制作用，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tgf - β下调，部分原因是影响了c-kit mRNA的稳定性。这些结果表明，c-kit在LT-HSC上的表达可能受到负调控。事实上，我们能够描述一种缺乏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，TGFbeta通过细胞内机制（包括转录因子和细胞周期调节蛋白的调节）阻止S期细胞周期的进展。体内实验结果表明，TGFbeta可以保护小鼠免受5-FU的致死性造血毒性和DXR的非造血毒性。这些发现表明，造血负调节因子可以成功地在体内系统地介导化学保护。先前许多实验室的结果也表明，在骨髓移植（BMT）前对供体细胞进行tgf β治疗可能通过阻断免疫反应性而产生有益的效果。我们能够通过tgfβ介导的机制显示同种异体骨髓移植后移植物抗宿主病（GVHD）的抑制。用tgf β和IL-10治疗供体CD4<sup+ t细胞使供体t细胞反应性降低，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 (TGFbeta) directly and reversibly inhibits hematopoietic stem cells with marrow repopulating ability (LT-HSC). Also, short-term incubation with antibody and antisense to TGFbeta stimulates the self-renewal potential of these stem cells. TGFbeta 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 TGFbeta, 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, TGFbeta 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 TGFbeta 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 TGFbeta 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 TGFbeta mediated mechanism. Treatment of donor CD4<sup+ T-cells with TGFbeta 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).