MACROPHAGE GROWTH: ROLE OF COLONY-STIMULATING FACTOR

巨噬细胞生长：集落刺激因子的作用

• 批准号: 3135689
• 负责人: BEN D CHEN
• 金额: $ 12.52万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-04-01 至 1994-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3135689
• 关键词: alveolar macrophages; bioassay; cell differentiation; cell growth regulation; cell population study; colony stimulating factor; cytokine receptors; flow cytometry; hematopoiesis; hematopoietic growth factor; hematopoietic stem cells; interleukin 1; laboratory mouse; laboratory rat; macrophage; monoclonal antibody; receptor expression; tissue /cell culture

The proliferation and differentiation of hematopoietic cells are dependent on the continuous presence of a group of growth factors known as colony-stimulating factors (CSFs). At least three known CSFs, Multi-CSF (IL-3), GM-CSF and M-CSF are involved in this process. Recent studies indicate that the action of CSFs is not restricted to hemopoietic precursor cells but includes the more mature macrophage progenitors, known as macrophage colony-forming cells (M-CFC), outside the bone marrow as well. Additionally, CSFs stimulate several functional aspects of mature macrophages, not related to proliferative activity. Murine alveolar M-CFC represent a unique cell population in that they can be induced by all three types of CSFs, either alone or in combination, to undergo clonal growth in vitro. This observation supports the concept that CSFs also play a key role in the regulation of macrophage production a the local level presumably through a paracrine mechanism. In this applicAtion, we will test this hypothesis and define the roles of CSF's in this process using murine alveolar macropohages as our working model. First, using reciprocal clone transfer experiments we will study the mechanisms in which various CSF's interact in the control of alveolar macrophage proliferation and differentiation and define the roles CSF's have in the generation of macrophage heterogeneity. We will then determine whether subsets of alveolar M-CFC exist and what is the relationship between these cells populations in terms of CSF receptor expression during their differentiation process. CSF- receptor bearing cells will be isolated and analyzed by using specific Anti-receptor antibodies and fluorescence-activated cell sorter (FACS) as well as autoradiography using iodinated CSFs. Next, we will study the ontogency of alveolar M-CFC in mice under both normal and pathologic conditions and determine whether they represent local macrophage progenitor cells with self-renewal potential. Finally, we will study the in vivo effect of recombinant CSFs as well as interleukin 1 (IL-1) on the production of alveolar macrophAges and local progenitor cells in both normal and irradiated or chemotherapy treated mice. The effect of CSFs in the regulation of functional activity of mature macrophages will also be examined.

造血细胞的增殖和分化是 依赖于一组生长因子的持续存在 称为集落刺激因子（CSF）。 至少有三个已知的 CSF、多种CSF（IL-3）、GM-CSF和M-CSF参与了这一过程。 过程 最近的研究表明，CSF的作用不是 仅限于造血前体细胞，但包括更多 成熟的巨噬细胞祖细胞，称为巨噬细胞集落形成 细胞（M-CFC），也在骨髓外。 此外，CSF 刺激成熟巨噬细胞的几个功能方面， 与增殖活性有关。 小鼠肺泡M-CFC代表一种独特的细胞群， 它们可以由所有三种类型的CSF单独或联合诱导。 组合，以进行体外克隆生长。 该观察结果 支持的概念，CSF也发挥了关键作用， 巨噬细胞产生的调节可能是局部水平的 通过旁分泌机制。 在本申请中，我们将测试 这一假设，并定义CSF在这一过程中的作用， 小鼠肺泡巨噬细胞作为我们的工作模型。 首先利用 相互克隆转移实验，我们将研究的机制 其中各种CSF在控制肺泡 巨噬细胞增殖和分化，并确定其作用 CSF在巨噬细胞异质性的产生中起作用。 我们将 然后确定肺泡M-CFC的子集是否存在， 这些细胞群在CSF方面的关系 在其分化过程中表达。 脑脊液- 将分离带有受体的细胞，并通过使用 特异性抗受体抗体和荧光激活细胞 分选仪（FACS）以及使用碘化CSF的放射自显影。 接下来，我们将研究小鼠肺泡M-CFC的个体发生率， 正常和病理条件，并确定他们是否 代表具有自我更新能力的局部巨噬细胞祖细胞 潜力 最后，我们将研究 重组CSF以及白细胞介素1（IL-1）对生产 肺泡巨噬细胞和局部祖细胞的正常 和辐射或化疗处理的小鼠。 CSF的影响 在调节成熟巨噬细胞的功能活性方面， 也要检查。