Yumine Ayako, Fraser Stuart T, Sugiyama Daisuke
Department of Research and Development of Next Generation Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
Department of Research and Development of Next Generation Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.; Disciplines of Physiology, Anatomy and Histology, School of Medical Sciences, University of Sydney, Sydney, Australia.
Blood Res. 2017 Mar;52(1):10-17. doi: 10.5045/br.2017.52.1.10. Epub 2017 Mar 27.
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 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 . 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.
红细胞的生成，即红细胞生成作用，在发育中的小鼠胚胎中以两个阶段进行：首先是原始红细胞生成，随后是定型红细胞生成。在小鼠胚胎中，原始红细胞生成和定型红细胞生成均起源于胚胎外卵黄囊。随着这些器官的形成，定型红细胞生成阶段的细胞随后迁移至胎儿肝脏、胎儿脾脏和胎儿骨髓。妊娠中期后，胎儿肝脏成为造血细胞扩增和红细胞成熟的主要器官。红细胞生成微环境表达关键细胞因子，如干细胞因子（SCF）、血小板生成素（TPO）以及胰岛素样生长因子IGF1和IGF2，支持胎儿肝脏中的造血扩增。此前，我们的研究小组证明，DLK1肝母细胞通过释放促红细胞生成素和SCF以及细胞外基质沉积来支持胎儿肝脏造血。小鼠胚胎中DLK1肝母细胞的缺失导致胎儿肝脏中造血细胞数量减少。编码蛋白酶和肽酶的基因在DLK1肝母细胞中高度表达。基于这一认识，并假设这些蛋白酶和肽酶正在产生小的、可能具有生物活性的肽，我们评估了一系列肽支持红细胞生成的能力。我们鉴定出KS-13（PCT/JP2010/067011）为一种促红细胞生成肽——一种能增强祖细胞产生红细胞能力的肽。在这里，我们讨论调节胚胎红细胞生成的因素，特别关注微环境细胞，并展示如何将这些知识应用于鉴定具有潜在治疗能力的微环境衍生肽。
