Weinreich Michael A, Lintmaer Ingrid, Wang Linlin, Liggitt H Denny, Harkey Michael A, Blau C Anthony
Division of Hematology, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
Blood. 2006 Dec 1;108(12):3713-21. doi: 10.1182/blood-2006-01-012278. Epub 2006 Aug 10.
Nearly 15 years have elapsed since the US Food and Drug Administration last approved a major new hematopoietic cytokine. Promiscuous binding to multiple receptors, or to receptors expressed by multiple tissues, reduces growth factor specificity and promotes side effects. Here we show that hematopoiesis can be differentially regulated using receptors rather than ligands. Conditional derivatives of both fibroblast growth factor receptor-1 (F36VFGFR1) and the thrombopoietin receptor (F36VMpl) induced a sustained expansion of mouse marrow cells ex vivo, and erythroid cells in vivo. Only F36VFGFR1 could support the ex vivo expansion of short-term repopulating hematopoietic stem cells (HSCs), the ex vivo survival of long-term repopulating HSCs, and the prolonged in vivo expansion of granulocytes, monocytes, and platelets. Only F36VMpl induced a response sufficiently rapid to accelerate recovery from radiation-induced anemia. These results establish receptors as a new class of hematopoietic regulators possessing activities unobtainable with growth factors.
自美国食品药品监督管理局上次批准一种重要的新型造血细胞因子以来，已经过去了近15年。与多种受体或多种组织表达的受体发生杂乱结合会降低生长因子的特异性并引发副作用。在此我们表明，可以利用受体而非配体对造血作用进行差异性调控。成纤维细胞生长因子受体-1（F36VFGFR1）和血小板生成素受体（F36VMpl）的条件性衍生物在体外诱导了小鼠骨髓细胞的持续扩增，并在体内诱导了红细胞的持续扩增。只有F36VFGFR1能够支持短期重建造血干细胞（HSC）的体外扩增、长期重建造血干细胞的体外存活以及粒细胞、单核细胞和血小板在体内的长期扩增。只有F36VMpl诱导的反应足够迅速，能够加速辐射诱导贫血后的恢复。这些结果确立了受体作为一类新型造血调节剂的地位，其具有生长因子无法实现的活性。
