Hematopoietic tissues, as a playground of receptor tyrosine kinases of the PDGF-receptor family

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Abstract

Three receptor tyrosine kinases of the PDGF receptor family (RTKP) that clustered within 1000 Kb of the mouse chromosome 5 constitute an interesting unit that are expressed in three distinct cell lineages essential for constructing hematopoietic tissues. Namely, the c-kit gene that is expressed in hematopoietic stem cells is flanked by pdgfrα and flk genes expressed respectively in stromal cells and vascular endothelial cells. In this article, we review our results on their expression in the embryonic hematopoietic tissues. We found that co-expression of Flkl and c-Kit was frequently detected either in vascular endothelial cells or hematopoietic cells in the early hematopoietic tissues. On the other hand, the three RTKPs are expressed in different cell lineages in the fetal liver. On the basis of this finding, we propose two modes of embryonic hematopoiesis; hematogenic angiopoiesis and hematopoiesis.

Section snippets

Nomenclature

RTKPreceptor tyrosine kinase of the PDGF receptor family;
AGMaorta-gonado-mesonephros;
OAomphalomesenteric artery;
UAumbilical artery;
DAdorsal aorta;
YSyolk 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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