Blood Res.  2017 Mar;52(1):10-17. 10.5045/br.2017.52.1.10.

Regulation of the embryonic erythropoietic niche: a future perspective

• Yumine A
• Fraser ST
• Sugiyama D

• KMID: 2375198
• DOI: http://doi.org/10.5045/br.2017.52.1.10

Abstract

The production of red blood cells, termed erythropoiesis, occurs in two waves in the developing mouse embryo: first primitive erythropoiesis followed by definitive erythropoiesis. In the mouse embryo, both primitive and definitive erythropoiesis originates in the extra-embryonic yolk sac. The definitive wave then migrates to the fetal liver, fetal spleen and fetal bone marrow as these organs form. The fetal liver serves as the major organ for hematopoietic cell expansion and erythroid maturation after mid-gestation. The erythropoietic niche, which expresses critical cytokines such as stem cell factor (SCF), thrombopoietin (TPO) and the insulin-like growth factors IGF1 and IGF2, supports hematopoietic expansion in the fetal liver. Previously, our group demonstrated that DLK1⁺ hepatoblasts support fetal liver hematopoiesis through erythropoietin and SCF release as well as extracellular matrix deposition. Loss of DLK1⁺ hepatoblasts in Map2k4(−/−) mouse embryos resulted in decreased numbers of hematopoietic cells in fetal liver. Genes encoding proteinases and peptidases were found to be highly expressed in DLK1⁺ hepatoblasts. Capitalizing on this knowledge, and working on the assumption that these proteinases and peptidases are generating small, potentially biologically active peptides, we assessed a range of peptides for their ability to support erythropoiesis in vitro. We identified KS-13 (PCT/JP2010/067011) as an erythropoietic peptide-a peptide which enhances the production of red blood cells from progenitor cells. Here, we discuss the elements regulating embryonic erythropoiesis with special attention to niche cells, and demonstrate how this knowledge can be applied in the identification of niche-derived peptides with potential therapeutic capability.

Keyword

Erythropoiesis; Embryo; Niche regulation; Cytokine peptide

MeSH Terms

Animals
Bone Marrow
Cytokines
Embryonic Structures
Erythrocytes
Erythropoiesis
Erythropoietin
Extracellular Matrix
Hematopoiesis
In Vitro Techniques
Liver
Mice
Peptide Hydrolases
Peptides
Somatomedins
Spleen
Stem Cell Factor
Stem Cells
Thrombopoietin
Yolk Sac
Cytokines
Erythropoietin
Peptide Hydrolases
Peptides
Somatomedins
Stem Cell Factor
Thrombopoietin

Figure

• 

  Fig. 1 Erythroid cell development in the mouse embryo. The sites for primitive and definitive erythropoiesis are shown. Arrows reveal presumable pathway of hematopoietic homing.Abbreviations: AGM, Aorta-Gonad-Mesonephros; BM, Bone Marrow; E, Embryonic day; PL, Placenta; YS, Yolk Sac.

• 

  Fig. 2 Embryonic hematopoietic niche. (A) Hematopoietic stem cells (arrow) are surrounded by the endothelial cells. Green: KIT, Red: CD31. (B) Hematopoietic stem/progenitor cells (arrows) are surrounded by hepatoblasts (arrow heads). Green: KIT, Red: DLK1.

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