Hematopoietic tissues, as a playground of receptor tyrosine kinases of the PDGF-receptor family
Section snippets
Nomenclature
RTKP receptor tyrosine kinase of the PDGF receptor family; AGM aorta-gonado-mesonephros; OA omphalomesenteric artery; UA umbilical artery; DA dorsal aorta; YS yolk sac.
Stem cell system including the hematopoietic tissue is defined as a system where the production and death of the cells continues in a coordinated manner throughout life. In a given stem cell system, proliferating cells are usually found in immature compartments, while cell death is a feature of fully mature compartments. In such a system, all stages earlier than actively proliferating stages constitute the stem cell compartment. Experiments of killing proliferating cells by ionizing radiation
Receptor Tyrosine Kinases of the PDGF Receptor Family (RTKP)
So far, 8 molecules of this family are known in both human and mouse, and they consist of an extracellular domain with 5 (Class III) or 7 (class V) immunoglobulin like domains, a transmembrane domain, and a cytoplasmic domain in which ATP-binding and kinase sites are split by a spacer 16, 17. Importantly, null mutations of the genes for either RTKP or their ligands are available to the exception of the flt4 gene, so that phenotype-gene correlation has been well documented for each member 18, 19
RTKPS Expression in the Early Hematopoietic Tissues
In the murine embryo, primary hematopoiesis appears at around E7.5 in the yolk sac 43, 44. It has been considered that the hematopoietic cells in the yolk sac then migrate to the developing liver at around E10.5 to establish a stem cell system for definitive hematopoiesis which by definition supplies all hematopoietic cells generated in later life 44, 45, 46.Recent studies indicated that the first stem cells for the definitive hematopoiesis appear in the Aorta-Gonad-Mesonephros (AGM) region
Overlaps in the Expression of RTKS
By a series of immunostaining in early embryos, we found that proximal lateral (splanchnic) mesoderm that express only Flk1 differentiates into two populations as early as E7.5; one is extraembryonic mesoderm where expression of both Flk1 and c-Kit is found and the other is lateral mesoderm where only Flk1 expression was detected [56]. According to the fate analysis, the former will give rise to yolk sac hemangioblasts, while the latter give rise to the embryonic vascular endothelial cells
Hematopoiesis and Hematogenic Angiopoiesis
One interesting feature of PDGFRα expression in the hematopoietic sites is that hematopoietic cells can contact directly with PDGFRα+ cells in the fetal liver, while no such contact was observed in earlier hematopoietic sites, though PDGFRα+ cells are present around large blood vessels. From these expression patterns, we would like to propose that the tissue organization in which hematopoietic cell contact occurs with PDGFRα+ mesenchymal cells, characterizes the site of hematopoiesis. In
Conclusion
Re-emerging controversy on the site of embryonic hematopoiesis tempted us to undertake immunohistological examination of the embryonic sites of hematopoiesis, expecting that it would provide insight into the tissue organization of early hematopoietic tissues. We present data showing that RTKs of PDGFR family is indeed a helpful tool to monitor three essential components of hematopoietic tissues, hematopoietic stem cells, vascular endothelial cells and stromal cells, both on a histological and
Acknowledgements
This study was supported by grants from the Japanese Ministry of Education, Science and Culture (No. 07CE2005, 07457085 and 06277103), a grant from the Ministry of Science and Technology (No. 13073-2125-14) a grant from RIKEN, and from Ono Pharmaceutical Co. Ltd.
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