Challier Cécile, Cocault Laurence, Berthier Rolande, Binart Nadine, Dusanter-Fourt Isabelle, Uzan Georges, Souyri Michèle
Institut National de la Santé et de la Recherche Médicale (INSERM) U506, Hôpital Paul Brousse, 14 avenue Paul-Vaillant Couturier, 94807 Villejuif Cedex, France.
Blood. 2002 Sep 15;100(6):2063-70.
The Mpl receptor plays an important role at the level of adult hematopoietic stem cells, but little is known of its function in embryonic and fetal hematopoiesis. We investigated the signals sent by the MPL cytoplasmic domain in fetal liver hematopoietic progenitors and during embryonic stem (ES) cell hematopoietic commitment. Mpl was found to be expressed only from day 6 of ES cell differentiation into embryoid bodies. Therefore, we expressed Mpl in undifferentiated ES cells or in fetal progenitors and studied the effects on hematopoietic differentiation. To avoid the inadvertent effect of thrombopoietin, we used a chimeric receptor, PM-R, composed of the extracellular domain of the prolactin receptor (PRL-R) and the transmembrane and cytoplasmic domains of Mpl. This allowed activation of the receptor with a hormone that is not involved in hematopoietic differentiation and assessment of the specificity of responses to Mpl by comparing PM-R with another PRL-R chimeric receptor that includes the cytoplasmic domain of the erythropoietin receptor (EPO-R) ([PE-R]). We have shown that the cytoplasmic domain of the Mpl receptor transduces exclusive signals in fetal liver hematopoietic progenitors as compared with that of EPO-R and that it promotes hematopoietic commitment of ES cells. Our findings demonstrate for the first time the specific role of Mpl in early embryonic or fetal hematopoietic progenitors and stem cells.
Mpl受体在成体造血干细胞水平发挥重要作用，但对其在胚胎和胎儿造血过程中的功能了解甚少。我们研究了MPL细胞质结构域在胎儿肝脏造血祖细胞以及胚胎干细胞（ES细胞）造血分化过程中发出的信号。发现Mpl仅在ES细胞分化为胚状体的第6天开始表达。因此，我们在未分化的ES细胞或胎儿祖细胞中表达Mpl，并研究其对造血分化的影响。为避免血小板生成素的意外影响，我们使用了一种嵌合受体PM-R，它由催乳素受体（PRL-R）的细胞外结构域以及Mpl的跨膜和细胞质结构域组成。这使得该受体能够被一种不参与造血分化的激素激活，并通过将PM-R与另一种包含促红细胞生成素受体（EPO-R）细胞质结构域的PRL-R嵌合受体（[PE-R]）进行比较，来评估对Mpl反应的特异性。我们已经表明，与EPO-R相比，Mpl受体的细胞质结构域在胎儿肝脏造血祖细胞中传递独特的信号，并且它促进ES细胞的造血分化。我们的研究结果首次证明了Mpl在早期胚胎或胎儿造血祖细胞和干细胞中的特定作用。
