Hematopoietic stem cells (HSCs) derived from human induced pluripotent stem cells (iPS cells) have important biomedical applications. We identified differentiation conditions that generate HSCs defined by robust long-term multilineage engraftment in immune-deficient NOD,B6.Prkdc^scid Il2rg^tm1Wjl/SzJ Kit^W41/W41 mice. We guided differentiating iPS cells, as embryoid bodies in a defined culture medium supplemented with retinyl acetate, through HOXA-patterned mesoderm to hemogenic endothelium specified by bone morphogenetic protein 4 and vascular endothelial growth factor (VEGF). Removal of VEGF facilitated an efficient endothelial-to-hematopoietic transition, evidenced by release into the culture medium of CD34⁺ blood cells, which were cryopreserved. Intravenous transplantation of two million thawed CD34⁺ cells differentiated from four independent iPS cell lines produced multilineage bone marrow engraftment in 25–50% of immune-deficient recipient mice. These functionally defined, multipotent CD34⁺ hematopoietic cells, designated iPS cell-derived HSCs (iHSCs), produced levels of engraftment similar to those achieved following umbilical cord blood transplantation. Our study provides a step toward the goal of generating HSCs for clinical translation.

源自人类诱导多能干细胞（iPS 细胞）的造血干细胞（HSC）具有重要的生物医学应用。我们确定了生成 HSC 的分化条件，这些条件是通过在免疫缺陷的 NOD、B6 中进行稳健的长期多谱系移植来定义的。 Prkdc ^scid Il2rg ^tm1Wjl/SzJ试剂盒^W41/W41小鼠。我们引导 iPS 细胞分化为补充有乙酸视黄酯的确定培养基中的胚状体，通过HOXA模式的中胚层分化为由骨形态发生蛋白 4 和血管内皮生长因子 (VEGF) 指定的造血内皮。 VEGF 的去除促进了内皮向造血的有效转变，这一点可以通过将 CD34 ⁺血细胞释放到冷冻保存的培养基中来证明。静脉内移植由四种独立的 iPS 细胞系分化而来的 200 万个解冻的 CD34 ⁺细胞，在 25-50% 的免疫缺陷受体小鼠中产生了多谱系骨髓移植。这些功能明确的多能 CD34 ⁺造血细胞，称为 iPS 细胞衍生的 HSC (iHSC)，产生的植入水平与脐带血移植后所达到的水平相似。我们的研究为生成用于临床转化的 HSC 的目标迈出了一步。