REGULATION OF NORMAL AND NEOPLASTIC HEMATOPOIETIC CELL GROWTH--ROLE OF BRMS

正常和肿瘤造血细胞生长的调节——BRMS 的作用

• 批准号: 3838187
• 负责人: F W RUSCETTI
• 金额: --
• 依托单位: DIVISION OF CANCER TREATMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3838187
• 关键词: biological response modifiers; cell growth regulation; clone cells; colony stimulating factor; cytokine receptors; growth factor receptors; growth inhibitors; hematopoiesis; hematopoietic growth factor; hematopoietic stem cells; human tissue; interleukin 3; monokines; receptor expression; single cell analysis; tissue /cell culture; transforming growth factors; tumor necrosis factor alpha

The overall goal of this section is to better understand the interactions between positive and negative regulators of hematopoietic stem cells. Synergistic effects of hematopoietic growth factors (HGFs) on BM growth and colony formation were consistently preceded by increased CSF receptor expression on enriched BM progenitor cells, but not on unfractionated cells. Upregulation of CSF receptor expression was observed after 6 hrs, maximal by 24 hrs and preceded detectable differentiation and did not require cell division since nocodazole, an inhibitor of mitosis, blocked CSF mediated cellular growth but not receptor upregulation. Single cell assays showed that growth factor synergy was a direct effect and correlated with the ability to upregulate CSF receptor expression. Furthermore, we have shown that TGF beta1 has bidirectional effects on hematopoietic progenitor cells; however, the mechanism(s) of action mediating these responses remain unknown. We have found that the effects of TGF beta1 on CSF-induced growth of BM progenitor cells is directly correlated with modulation of CSF receptor expression. Specifically, TGF beta1 mediated inhibition of IL 3-stimulated BM proliferation was preceded by reduced IL 3 receptor expression, while upregulation of GM-CSF receptors preceded the synergistic effect of TGF beta1 on GM-CSF-stimulated proliferation. Similarly, TNF alpha has been reported to either inhibit or stimulate CSF-induced hematopoietic progenitor cell growth. We found that the direct effects of TNF alpha on the murine BMC and enriched multipotential progenitors are only inhibitory, and correlated with its ability to transdown-modulate the receptor expression for the CSFs. Also, MIP 1alpha was shown to directly enhance IL 3- and GM-CSF-induced growth of Lin- cells in single cell assays. However, MIP 1alpha like TGF beta1 inhibited both the IL 3 and GM-CSF-induced growth of more primitive Lin-, Thy-1+ cells. Thus, modulation of growth factor receptor expression and direct bidirectional effects are common features in cytokine regulation of primitive hematopoietic cell growth.

本节的总体目标是更好地理解 造血正、负调节因子间的相互作用 干细胞 造血生长因子（HGF）的协同作用 对BM生长和集落形成的影响一致， 在富集的BM祖细胞上增加CSF受体表达，但是 而不是普通细胞。 CSF受体表达上调 在6小时后观察到，24小时最大， 分化，不需要细胞分裂，因为诺考达唑， 有丝分裂抑制剂，阻断CSF介导的细胞生长，但不 受体上调。 单细胞测定显示生长因子 协同作用是一个直接的影响，并与能力， 上调CSF受体表达。 此外，我们已经表明，TGF β 1对造血祖细胞具有双向作用; 然而，调节这些反应的作用机制仍然存在， 未知 我们发现TGF β 1对CSF诱导的细胞增殖的影响 骨髓祖细胞的生长与调节 CSF受体表达。 具体地说，TGF β 1介导的抑制 IL 3刺激的骨髓增殖之前，IL 3受体减少 表达，而GM-CSF受体的上调先于表达。 TGF β 1对GM-CSF刺激增殖的协同作用。 同样，据报道TNF α抑制或刺激 CSF诱导的造血祖细胞生长。 我们发现 TNF α对小鼠BMC的直接影响， 多能祖细胞仅具有抑制作用，并与其 转录下调CSF受体表达的能力。 MIP 1 α还能直接增强IL 3和GM-CSF诱导的 在单细胞测定中Lin-细胞的生长。 然而，MIP 1alpha样 TGF β 1抑制了IL 3和GM-CSF诱导的更多细胞的生长， 原始Lin-、Thy-1+细胞。 因此，生长因子的调节 受体表达和直接双向效应是共同的特征 原始造血细胞生长的细胞因子调节。