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

本节的总体目标是更好地理解 正、负性造血调节因子的相互作用 干细胞。造血生长因子的协同作用 在BM的生长和克隆形成之前一直是 丰富的BM祖细胞上的CSF受体表达增加，但 不是在未分离的细胞上。脑脊液受体表达上调 在6小时后观察到，最大值为24小时，在可检测之前 分化，不需要细胞分裂，因为诺康唑，一个 有丝分裂抑制物，阻断脑脊液介导的细胞生长，但不是 受体上调。单细胞分析显示生长因子 协同效应是一种直接效应，与 上调脑脊液受体的表达。此外，我们已经证明，转化生长因子 β1对造血祖细胞具有双向作用； 然而，调解这些反应的行动机制(S)仍然存在 未知。我们发现转化生长因子β1对脑脊液诱导的 BM祖细胞的生长与细胞周期调控有直接关系 脑脊液受体表达。具体地说，转化生长因子β1介导的抑制 在IL-3刺激的BM增殖之前，IL-3受体减少 表达，而GM-CSF受体上调先于 转化生长因子β1对GM-CSF刺激的细胞增殖的协同作用。 同样，据报道，肿瘤坏死因子α可抑制或刺激 脑脊液诱导造血祖细胞生长。我们发现， 肿瘤坏死因子α对小鼠骨髓基质细胞的直接作用及浓缩作用 多潜能祖细胞仅具有抑制性，并与其相关 转录下调CSF受体表达的能力。 此外，MIP-1α还可直接增强IL-3和GM-CSF诱导的 单细胞培养法检测LIN-细胞的生长。然而，MIP 1类似于 转化生长因子β1抑制IL-3和GM-CSF诱导的巨噬细胞生长 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常见的特征 在原始造血细胞生长的细胞因子调节中。

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.