Chemically-defined generation of human hemogenic endothelium and definitive hematopoietic progenitor cells.
Chemically-defined generation of human hemogenic endothelium and definitive hematopoietic progenitor cells.
复制标题
DOI：
10.1016/j.biomaterials.2022.121569
复制
发表时间：
2022-06
期刊：
影响因子：
14
通讯作者：
中科院分区：
文献类型：
--
作者：
人类造血干细胞（HSC）源自主动脉-性腺-中肾（AGM），广泛用于治疗血液疾病和癌症。然而，仍然缺乏在体外稳健生成它们的技术。在这里，我们证明 Wnt 信号传导的时间操纵对于诱导人类多能干细胞的 AGM 样造血作用是充分且必要的。在主动脉样SOX17+CD235a−造血内皮阶段抑制TGFβ产生了AGM样造血祖细胞，其在转录水平上与原代脐带血HSC非常相似，并且通过单细胞RNA测序分析包含不同谱系引发的祖细胞群。值得注意的是，所得的定形细胞在体外表现出淋巴和骨髓细胞的潜力。可以定位斑马鱼的明确造血部位，并在移植后拯救无血的斑马鱼。在小鼠受体中也观察到了移植和多谱系再增殖活动。我们的工作共同提供了一个化学成分确定且无饲养层的培养平台，用于可扩展地生成类似 AGM 的造血祖细胞，从而增强了用于各种治疗应用的功能性血液和免疫细胞的生产。
Human hematopoietic stem cells (HSCs), which arise from aorta-gonad-mesonephros (AGM), are widely used to treat blood diseases and cancer. However, a technique for their robust generation in vitro is still missing. Here we show temporal manipulation of Wnt signaling is sufficient and essential to induce AGM-like hematopoiesis from human pluripotent stem cells. TGFβ inhibition at the stage of aorta-like SOX17+CD235a− hemogenic endothelium yielded AGM-like hematopoietic progenitors, which closely resembled primary cord blood HSCs at the transcriptional level and contained diverse lineage-primed progenitor populations via single cell RNA-sequencing analysis. Notably, the resulting definitive cells presented lymphoid and myeloid potential in vitro; and could home to a definitive hematopoietic site in zebrafish and rescue bloodless zebrafish after transplantation. Engraftment and multilineage repopulating activities were also observed in mouse recipients. Together, our work provided a chemically-defined and feeder-free culture platform for scalable generation of AGM-like hematopoietic progenitor cells, leading to enhanced production of functional blood and immune cells for various therapeutic applications.
登录
查看更多内容
影响因子：
21.3
作者：
Ditadi A;Sturgeon CM;Tober J;Awong G;Kennedy M;Yzaguirre AD;Azzola L;Ng ES;Stanley EG;French DL;Cheng X;Gadue P;Speck NA;Elefanty AG;Keller G
通讯作者：
Keller G
影响因子：
64.8
作者：
Chen JY;Miyanishi M;Wang SK;Yamazaki S;Sinha R;Kao KS;Seita J;Sahoo D;Nakauchi H;Weissman IL
通讯作者：
Weissman IL
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
11.8
作者：
Dege, Carissa;Fegan, Katherine H.;Sturgeon, Christopher M.
通讯作者：
Sturgeon, Christopher M.