Wiktor-Jedrzejczak W W, Ahmed A, Szczylik C, Skelly R R
J Exp Med. 1982 Nov 1;156(5):1516-27. doi: 10.1084/jem.156.5.1516.
Compared with normal littermates, the op/op mice had very few macrophages in the peritoneal cavity and severely reduced numbers of monocytes in the peripheral blood. Moreover, osteopetrotic animals demonstrated an altered distribution of hemopoietic tissue with a 10-fold decrease in the number of marrow cells. Liver hemopoiesis persisted in 4-wk-old mice as evidenced by the presence of hemopoietic stem cells (HSC). Moreover, the concentration of HSC was decreased in marrow and increased in the spleen of op/op mice. In spite of the paucity of cells of monocyte-macrophage lineage in vivo, progenitor cells from hemopoietic tissues of op/op mice formed increased numbers of monocyte-macrophage colonies in vitro in the presence of exogenous colony-stimulating activity (CSA). The source of this critical CSA was a medium conditioned by stromal fibroblastoid colonies formed in vitro by normal marrow cells. Therefore, these data suggest that op/op mice possess normal monocyte-macrophage-osteoclast progenitor cells but these cells are unable to fully differentiate in the op/op mouse microenvironment. In support of this, in cultures of stromal fibroblastoid colonies from op/op marrow or spleen, the concomitant growth of macrophages, normally very dense, was drastically reduced. Moreover, transplantation of op/op spleen cells into lethally irradiated littermate recipients resulted in their hemopoietic reconstitution without signs of macrophage defect. Thus, the op/op splenic cells do not transfer the disease and are capable of normal differentiation in normal in vivo environment. These observations support the hypothesis that the defect in op/op mice is a result of the failure of hemopoietic stromal fibroblastoid cells to release sufficient amounts of CSA necessary for normal differentiation of cells of the monocyte-macrophage lineage.
与正常同窝小鼠相比，op/op小鼠腹腔内的巨噬细胞极少，外周血中的单核细胞数量也严重减少。此外，骨硬化动物的造血组织分布改变，骨髓细胞数量减少了10倍。4周龄小鼠的肝脏造血持续存在，造血干细胞（HSC）的存在证明了这一点。此外，op/op小鼠骨髓中的HSC浓度降低，脾脏中的HSC浓度升高。尽管体内单核细胞-巨噬细胞谱系的细胞数量稀少，但在存在外源性集落刺激活性（CSA）的情况下，op/op小鼠造血组织中的祖细胞在体外形成的单核细胞-巨噬细胞集落数量增加。这种关键CSA的来源是由正常骨髓细胞在体外形成的基质成纤维细胞样集落所条件化的培养基。因此，这些数据表明op/op小鼠拥有正常的单核细胞-巨噬细胞-破骨细胞祖细胞，但这些细胞在op/op小鼠的微环境中无法完全分化。支持这一点的是，在op/op骨髓或脾脏的基质成纤维细胞样集落培养物中，通常非常密集的巨噬细胞的伴随生长大幅减少。此外，将op/op脾细胞移植到经致死性照射的同窝受体中，导致它们的造血重建，没有巨噬细胞缺陷的迹象。因此，op/op脾细胞不会传播疾病，并且能够在正常的体内环境中正常分化。这些观察结果支持了这样的假设，即op/op小鼠的缺陷是由于造血基质成纤维细胞样细胞未能释放足够量的CSA，而CSA是单核细胞-巨噬细胞谱系细胞正常分化所必需的。
