Kimura S, Roberts A W, Metcalf D, Alexander W S
The Walter and Eliza Hall Institute for Medical Research and The Cooperative Research Centre for Cellular Growth Factors. PO Royal Melbourne Hospital, Victoria 3050, Australia.
Proc Natl Acad Sci U S A. 1998 Feb 3;95(3):1195-200. doi: 10.1073/pnas.95.3.1195.
Thrombopoietin (TPO) acts as a lineage-specific late-acting factor to stimulate megakaryocyte and platelet formation. However, analysis of mice lacking either the cytokine or its receptor, c-Mpl, also revealed deficiencies in progenitor cells of multiple hematopoietic lineages, suggesting that TPO signaling may play an important role in the regulation of the hematopoietic stem cell compartment. To investigate this hypothesis, we determined preprogenitor and colony forming unit-spleen (CFU-S) numbers and analyzed the long-term hematopoietic repopulating capacity of bone marrow cells from mpl-/- mice. mpl-/- mice had 4- to 12-fold fewer preprogenitor cells than wild-type mice. In irradiated normal recipients, mpl-/- bone marrow generated 8- to 10-fold fewer spleen colonies than wild-type marrow at both 8 and 12 days after transplantation. This defect was intrinsic to the transplanted hematopoietic cells, as the microenvironment of mpl-/- recipients supported similar CFU-S growth to that observed in wild-type recipients. In definitive assays of stem cell function, bone marrow cells from mpl-/- mice failed to compete effectively with normal cells for long-term reconstitution of the hematopoietic organs of irradiated recipients, even when transplanted in 10-fold excess. Serial transplantation studies further suggested that stem cell self-renewal also may be compromised in mpl-/- mice. These data imply that TPO, signaling through c-Mpl, plays a vital physiological role in the regulation of hematopoietic stem cell production and function.
血小板生成素（TPO）作为一种谱系特异性晚期作用因子，可刺激巨核细胞和血小板的形成。然而，对缺乏该细胞因子或其受体c-Mpl的小鼠进行分析后发现，多种造血谱系的祖细胞也存在缺陷，这表明TPO信号传导可能在造血干细胞区室的调节中发挥重要作用。为了验证这一假设，我们测定了前祖细胞和脾集落形成单位（CFU-S）的数量，并分析了mpl-/-小鼠骨髓细胞的长期造血重建能力。mpl-/-小鼠的前祖细胞数量比野生型小鼠少4至12倍。在接受辐照的正常受体中，移植后8天和12天，mpl-/-骨髓产生的脾集落比野生型骨髓少8至10倍。这种缺陷是移植的造血细胞所固有的，因为mpl-/-受体的微环境支持与野生型受体相似的CFU-S生长。在干细胞功能的确定性检测中，即使以10倍的过量移植，mpl-/-小鼠的骨髓细胞也无法与正常细胞有效竞争，以长期重建辐照受体的造血器官。连续移植研究进一步表明，mpl-/-小鼠的干细胞自我更新能力也可能受损。这些数据表明，通过c-Mpl传导信号的TPO在造血干细胞的产生和功能调节中起着至关重要的生理作用。
