Kaushansky Kenneth
Department of Medicine, University of California, San Diego, San Diego, California 92103, USA.
Ann N Y Acad Sci. 2003 May;996:39-43. doi: 10.1111/j.1749-6632.2003.tb03230.x.
Although it is clear that thrombopoietin is the primary regulator of thrombopoiesis, several lines of evidence indicate that the hormone affects multiple aspects of hematopoiesis: the in vivo administration of TPO increases marrow levels of erythroid, myeloid, and megakaryocytic progenitor cells and its genetic elimination or that of its receptor (c-mpl) reduces the numbers of these cells; all hematopoietic stem cells (HSCs) are c-mpl+; genetic elimination of c-mpl reduces the numbers of murine HSCs by 7-8-fold; and its null mutation in humans leads to congenital amegakaryocytic thrombocytopenia, a disorder that almost invariably leads to aplastic anemia. Recently, we have begun to explore the role of TPO in the HSC self-renewal and expansion that characterizes the post-stem-cell-transplantation period. Using limiting dilution cell transplantation analyses, we found that HSC self-renewal and expansion is reduced 10-20-fold after transplantation of normal stem cells into tpo null mice compared to their wild-type counterparts. Although the molecular mechanisms responsible for these findings are only now being explored, it is expected that a greater understanding of the roles played by TPO in HSC physiology will lead to novel therapeutic opportunities.
虽然血小板生成素显然是血小板生成的主要调节因子，但有几条证据表明该激素会影响造血作用的多个方面：在体内给予血小板生成素会增加红系、髓系和巨核系祖细胞的骨髓水平，而对其进行基因剔除或剔除其受体（c-mpl）会减少这些细胞的数量；所有造血干细胞（HSC）均为c-mpl阳性；对c-mpl进行基因剔除会使小鼠造血干细胞数量减少7至8倍；而其在人类中的无效突变会导致先天性无巨核细胞血小板减少症，这种病症几乎总会导致再生障碍性贫血。最近，我们已开始探究血小板生成素在造血干细胞自我更新和扩增中的作用，这是干细胞移植后阶段的特征。通过有限稀释细胞移植分析，我们发现，与野生型对照相比，将正常干细胞移植到血小板生成素基因敲除小鼠体内后，造血干细胞的自我更新和扩增减少了10至20倍。虽然造成这些结果的分子机制目前才刚开始探究，但预计对血小板生成素在造血干细胞生理学中所起作用的更深入了解将带来新的治疗机会。
