The bloody fate of endothelial stem cells
Molecular/Cancer Biology Laboratory, Haartman Institute, Helsinki University Central Hospital and Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland\, http://www.100md.com
Introduction\, http://www.100md.com
In the embryo, the decision to become an endothelial cell (EC) is a bold choice that commits a cell to the task of generating the blood and lymphatic vascular systems, which form one of the most important and complex organs in the mammalian body. Embryonic blood vessel formation is guided by incompletely understood developmental cues, which give rise to a vascular network with remarkable precision and reproducibility with respect to the network's organization, branching pattern, treelike hierarchy of vessel sizes, and formation of arteries, veins, and lymphatic vessels (Risau 1997; Weinstein 1999). The decision of choosing a hematopoietic cell (HPC) fate is an equally complex undertaking. Yet, the blood circulatory system formed principally by these two differentiation lineages and by the cardiogenic mesenchyme is the first functional organ system formed during embryonic development.
During early mouse embryogenesis, starting at embryonic day 7.5 (E7.5), HPCs are generated in a close association with the developing vascular system. In the blood islands of the yolk sac where the earliest HPCs appear, both HPC and EC lineages arise almost simultaneously from extraembryonic mesoderm, forming structures in which primitive erythrocytes are surrounded by a layer of angioblasts that give rise to differentiated ECs. The close temporal and spatial relationship of hematopoietic and vascular development led to the hypothesis that the two lineages arise from a common precursor, the hemangioblast (Sabin 1920; Murray 1932). This concept is supported by the shared expression of a number of different genes by both lineages. In contrast to commonly used endothelial markers such as CD34 and Tie2 that are also expressed in adult hematopoietic stem cells (HSCs), Flk1/vascular endothelial growth factor (VEGF) receptor-2 (hereafter VEGFR-2) expression is unique in that it is restricted to the mesodermal precursor cells and ECs, and is down-regulated in HPCs (Risau 1997). It is now well established that VEGFR-2+ cells represent a common precursor for ECs and HPCs (Kennedy et al. 1997; Choi et al. 1998; Nishikawa et al. 1998). However, the pathway downstream of VEGFR-2 signaling has not been established in the hemangioblasts. In this issue of Genes & Development, Ema and colleagues (2003) demonstrate that the transcription factor Tal1/SCL (T-cell acute leukemia/stem cell leukemia) regulates the choice of cell fate in early development into EC, HPC, and smooth muscle cell (SMC) lineages. These results provide an important additional piece into the emerging tentative differentiation scheme of embryonic and adult HPCs and ECs (
fig.ommitted!'$(f0}, 百拇医药
. A schematic view of possible developmental lineage relationships of embryonic and adult hematopoietic and endothelial cells. During embryogenesis, the lateral mesoderm or "hemangioblasts" derived from the mesoderm give rise to both primitive hematopoietic (HPC) and endothelial (EC) cell lineages. Part of the pericytes/smooth muscle cells (PC/SMCs) are apparently derived from the ECs. The origin of the definitive (adult-type) HPCs in embryos is not clear, and different views have been presented ranging between the concepts of "definitive hemangioblast" and "hemogenic EC" (delineated by broken lines). After the embryonic differentiation of the arterial and venous endothelial cells (BEC), lymphatic endothelial cells (LECs) are generated from the latter. In adults, the discovery of circulating EC progenitors (CEP), derived from hemangioblastic cells or the hematopoietic stem cells (HSCs), has suggested that adult angiogenesis may operate in part by similar mechanisms as in the embryos. A blood vessel is shown on the right, with an indication of the corresponding constituent cells. The expression of VEGFR-2 (Y) and Tal1 (in red, low-level in pink) in the cells has been marked.
Critical events in the establishment of the circulatory systemy, 百拇医药
Several results indicate that vascular development may be to a large extent genetically determined and that major problems in vascular network formation are lethal in early postimplantation development, whereas the proper vessel integrity and hemodynamic vascular functions are important throughout embryonic and adult life. Deletion of the Vegfr2 gene abruptly ends both HPC and EC differentiation in embryos, whereas VEGF promotes angioblast differentiation (Shalaby et al. 1995; Carmeliet et al. 1996; Ferrara et al. 1996; Eichmann et al. 1997). In contrast, the other VEGF receptor, VEGFR-1, suppresses hemangioblast commitment into ECs (Fong et al. 1995, 1999). In the embryo, the basic fibroblast growth factor FGF-2 is also involved in the induction of angioblasts from the mesoderm (Flamme and Risau 1992; Cox and Poole 2000). Following the commitment to the EC lineage, the angioblasts cluster and reorganize to form capillary-like tubes. They may migrate extensively during the enlargement and remodeling of the plexus, which involves the sprouting, splitting, fusion, and regression (pruning) of branches that shape the organ-specific vascular hierarchy with directional blood flow. In the process of differentiation into arterial or venous structures, the ECs become surrounded to various degrees by pericytes (PCs) and SMCs with the formation of a pericellular basal lamina that gives support to the vessels. In pathological angiogenesis, the maturation and stabilization of the vessels occur improperly, and the vessels remain immature (Hashizume et al. 2002).
Genetic studies in the zebrafish have shown molecular differences between the arterial and venous ECs even before vessel formation. For example, signals mediated by the Notch1 receptor induce expression of the basic helix-loop-helix transcriptional repressor gridlock, which commits angioblasts to the arterial fate (Lawson et al. 2001; Zhong et al. 2001). VEGF acts upstream of Notch but downstream of the sonic hedgehog gene in arterial differentiation (Lawson et al. 2002). Members of the ephrin family and their corresponding Eph receptors are also important determinants of arterial and venous vessel identity and arterio-venous boundaries during embryonic development (Wang et al. 1998; Adams et al. 1999). The full understanding of the molecular signaling pathways for the commitment to the HPC and EC fates and for EC differentiation is important not only for the understanding of the normal vascular development but also because of the involvement of the reactivation of angiogenic pathways in various diseases.
Following the initial process of primitive hematopoiesis, the site of definitive hematopoiesis shifts to the fetal liver at midgestation, and finally to the bone marrow (BM). Although the origin of the definitive HSCs is still controversial, the aorta-gonad-mesonephros (AGM) region in the mouse and splanchonopleura in the chick are widely accepted as their sites of origin (Muller et al. 1994; Cumano et al. 1996; Medvinsky and Dzierzak 1996). The intraembryonic origin of definitive hematopoiesis is supported by observations of clusters of HPCs that are attached to the ventral wall of the dorsal aorta, as if they were budding from the ECs (Emmel 1915; Oberlin et al. 2002). It was proposed that at least a certain portion of the definitive HPC lineage derives from the ECs in chicks, and in mice, vascular endothelial cadherin-positive cells sorted from the AGM region are capable of reconstituting BM hematopoiesis in irradiated adult mice (Jaffredo et al. 1998; North et al. 2002).+l$1o-%, 百拇医药
Capturing the elusive hemangioblast--- a hemogenic endothelial cell?(Hajime Kubo and Kari Alitalo)
Introduction\, http://www.100md.com
In the embryo, the decision to become an endothelial cell (EC) is a bold choice that commits a cell to the task of generating the blood and lymphatic vascular systems, which form one of the most important and complex organs in the mammalian body. Embryonic blood vessel formation is guided by incompletely understood developmental cues, which give rise to a vascular network with remarkable precision and reproducibility with respect to the network's organization, branching pattern, treelike hierarchy of vessel sizes, and formation of arteries, veins, and lymphatic vessels (Risau 1997; Weinstein 1999). The decision of choosing a hematopoietic cell (HPC) fate is an equally complex undertaking. Yet, the blood circulatory system formed principally by these two differentiation lineages and by the cardiogenic mesenchyme is the first functional organ system formed during embryonic development.
During early mouse embryogenesis, starting at embryonic day 7.5 (E7.5), HPCs are generated in a close association with the developing vascular system. In the blood islands of the yolk sac where the earliest HPCs appear, both HPC and EC lineages arise almost simultaneously from extraembryonic mesoderm, forming structures in which primitive erythrocytes are surrounded by a layer of angioblasts that give rise to differentiated ECs. The close temporal and spatial relationship of hematopoietic and vascular development led to the hypothesis that the two lineages arise from a common precursor, the hemangioblast (Sabin 1920; Murray 1932). This concept is supported by the shared expression of a number of different genes by both lineages. In contrast to commonly used endothelial markers such as CD34 and Tie2 that are also expressed in adult hematopoietic stem cells (HSCs), Flk1/vascular endothelial growth factor (VEGF) receptor-2 (hereafter VEGFR-2) expression is unique in that it is restricted to the mesodermal precursor cells and ECs, and is down-regulated in HPCs (Risau 1997). It is now well established that VEGFR-2+ cells represent a common precursor for ECs and HPCs (Kennedy et al. 1997; Choi et al. 1998; Nishikawa et al. 1998). However, the pathway downstream of VEGFR-2 signaling has not been established in the hemangioblasts. In this issue of Genes & Development, Ema and colleagues (2003) demonstrate that the transcription factor Tal1/SCL (T-cell acute leukemia/stem cell leukemia) regulates the choice of cell fate in early development into EC, HPC, and smooth muscle cell (SMC) lineages. These results provide an important additional piece into the emerging tentative differentiation scheme of embryonic and adult HPCs and ECs (
fig.ommitted!'$(f0}, 百拇医药
. A schematic view of possible developmental lineage relationships of embryonic and adult hematopoietic and endothelial cells. During embryogenesis, the lateral mesoderm or "hemangioblasts" derived from the mesoderm give rise to both primitive hematopoietic (HPC) and endothelial (EC) cell lineages. Part of the pericytes/smooth muscle cells (PC/SMCs) are apparently derived from the ECs. The origin of the definitive (adult-type) HPCs in embryos is not clear, and different views have been presented ranging between the concepts of "definitive hemangioblast" and "hemogenic EC" (delineated by broken lines). After the embryonic differentiation of the arterial and venous endothelial cells (BEC), lymphatic endothelial cells (LECs) are generated from the latter. In adults, the discovery of circulating EC progenitors (CEP), derived from hemangioblastic cells or the hematopoietic stem cells (HSCs), has suggested that adult angiogenesis may operate in part by similar mechanisms as in the embryos. A blood vessel is shown on the right, with an indication of the corresponding constituent cells. The expression of VEGFR-2 (Y) and Tal1 (in red, low-level in pink) in the cells has been marked.
Critical events in the establishment of the circulatory systemy, 百拇医药
Several results indicate that vascular development may be to a large extent genetically determined and that major problems in vascular network formation are lethal in early postimplantation development, whereas the proper vessel integrity and hemodynamic vascular functions are important throughout embryonic and adult life. Deletion of the Vegfr2 gene abruptly ends both HPC and EC differentiation in embryos, whereas VEGF promotes angioblast differentiation (Shalaby et al. 1995; Carmeliet et al. 1996; Ferrara et al. 1996; Eichmann et al. 1997). In contrast, the other VEGF receptor, VEGFR-1, suppresses hemangioblast commitment into ECs (Fong et al. 1995, 1999). In the embryo, the basic fibroblast growth factor FGF-2 is also involved in the induction of angioblasts from the mesoderm (Flamme and Risau 1992; Cox and Poole 2000). Following the commitment to the EC lineage, the angioblasts cluster and reorganize to form capillary-like tubes. They may migrate extensively during the enlargement and remodeling of the plexus, which involves the sprouting, splitting, fusion, and regression (pruning) of branches that shape the organ-specific vascular hierarchy with directional blood flow. In the process of differentiation into arterial or venous structures, the ECs become surrounded to various degrees by pericytes (PCs) and SMCs with the formation of a pericellular basal lamina that gives support to the vessels. In pathological angiogenesis, the maturation and stabilization of the vessels occur improperly, and the vessels remain immature (Hashizume et al. 2002).
Genetic studies in the zebrafish have shown molecular differences between the arterial and venous ECs even before vessel formation. For example, signals mediated by the Notch1 receptor induce expression of the basic helix-loop-helix transcriptional repressor gridlock, which commits angioblasts to the arterial fate (Lawson et al. 2001; Zhong et al. 2001). VEGF acts upstream of Notch but downstream of the sonic hedgehog gene in arterial differentiation (Lawson et al. 2002). Members of the ephrin family and their corresponding Eph receptors are also important determinants of arterial and venous vessel identity and arterio-venous boundaries during embryonic development (Wang et al. 1998; Adams et al. 1999). The full understanding of the molecular signaling pathways for the commitment to the HPC and EC fates and for EC differentiation is important not only for the understanding of the normal vascular development but also because of the involvement of the reactivation of angiogenic pathways in various diseases.
Following the initial process of primitive hematopoiesis, the site of definitive hematopoiesis shifts to the fetal liver at midgestation, and finally to the bone marrow (BM). Although the origin of the definitive HSCs is still controversial, the aorta-gonad-mesonephros (AGM) region in the mouse and splanchonopleura in the chick are widely accepted as their sites of origin (Muller et al. 1994; Cumano et al. 1996; Medvinsky and Dzierzak 1996). The intraembryonic origin of definitive hematopoiesis is supported by observations of clusters of HPCs that are attached to the ventral wall of the dorsal aorta, as if they were budding from the ECs (Emmel 1915; Oberlin et al. 2002). It was proposed that at least a certain portion of the definitive HPC lineage derives from the ECs in chicks, and in mice, vascular endothelial cadherin-positive cells sorted from the AGM region are capable of reconstituting BM hematopoiesis in irradiated adult mice (Jaffredo et al. 1998; North et al. 2002).+l$1o-%, 百拇医药
Capturing the elusive hemangioblast--- a hemogenic endothelial cell?(Hajime Kubo and Kari Alitalo)