造血幹細胞の発生とその微小環境

Abstract

The association between hematopoietic stem cells and their microenvironment is central to the development and maintenance of a functional hematopoietic system. The TIE2/TEK receptor tyrosine kinase and its ligands, Angiopoietin-1 and-2, have been shown to be involved in the formation of the embryonic vasculature. Although the defect of vasculo-angiogenesis was confirmed in both knockout mice of TIE2 and Angiopoietin-1, the precise function of these molecules is not well understood. Here, we evaluated the expression and function of TIE2 in the para-aortic splanchnopleural mesoderm (P-Sp) during embryogenesis, and especially in the omphalomesenteric artery and vitelline artery. In the vitelline artery at 9.5 days postcoitum (dpc), TIE2+ hematopoietic cells aggregated and adhered to TIE2+ endothelial cells. Soluble TIE2-Fc chimeric protein inhibited the development of hematopoiesis and angiogenesis in the P-Sp explant culture, and TIE2-deficient mice showed severely impaired definitive hematopoiesis. An in vitro study revealed that Angiopoietin-1 and -2 promoted the adhesion to fibronectin (FN) through integrins and cell-cell adhesion in TIE2-transfected cells. Finally, we showed that Angiopoietin-1 enhanced the adhesion of TIE2+ primary cells sorted from 9.5 dpc P-Sp to FN. These data demonstrate the TIE2-Angiopoietin signals play a critical role in the development of definitive hematopoiesis, as well as that of angio-vasculogenesis.