Luo Qian, Chen Yijin, Li Honghu, Long Yan, Shan Wei, Zeng Xiangjun, Cai Shuyang, Meng Ye, Wei Cong, Xu Yulin, Tie Ruxiu, Luo Yi, Qian Pengxu, Zhang Meng, Huang He
Bone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China.
Institute of Hematology, Zhejiang University, Hangzhou, China.
Exp Mol Med. 2025 Jun 2. doi: 10.1038/s12276-025-01473-6.
Human embryonic stem cells (hESCs) serve as an ideal cell source for generating hematopoietic stem cells (HSCs). In embryonic hematopoiesis, hemogenic endothelium has been identified as a source of HSCs, yet the regulatory mechanisms remain elusive. Here, through dynamic gene expression profiling analysis and verification, we find that ELTD1 expression parallels genes related to the specification of hemogenic endothelium progenitors (HEPs) from hESCs and is highly expressed in the HEPs. We then investigate the impact of ELTD1 on the hematopoietic differentiation of hESCs via gain- and loss-of-function experiments. Knockdown or deletion of ELTD1 mediates hESC hematopoiesis by specifically facilitating the generation of HEPs, thus promoting endothelial-to-hematopoietic transition to generate more hematopoietic cells. Besides, the overexpression of ELTD1 serves to further solidify this conclusion. Mechanistically, we demonstrate that ELTD1 exerts its function through the Wnt signaling pathway by bioinformatic analyses and functional studies. In addition, our results demonstrate a protein-protein interaction between ELTD1 and HPIP and further reveal that HPIP modulates the Wnt signaling pathway through LEF1. Collectively, these findings indicate that the ELTD1-HPIP-LEF1-Wnt regulatory axis acts as a novel mechanism regulating HEP generation during early hematopoietic differentiation of hESCs, providing new insights into the molecular mechanisms underlying human hematopoiesis.
人类胚胎干细胞（hESCs）是生成造血干细胞（HSCs）的理想细胞来源。在胚胎造血过程中，造血内皮已被确定为HSCs的来源，但其调控机制仍不清楚。在这里，通过动态基因表达谱分析和验证，我们发现ELTD1的表达与从hESCs分化为造血内皮祖细胞（HEPs）相关的基因平行，并且在HEPs中高表达。然后，我们通过功能获得和功能缺失实验研究了ELTD1对hESCs造血分化的影响。敲低或缺失ELTD1通过特异性促进HEPs的生成来介导hESCs的造血作用，从而促进内皮向造血的转变以产生更多的造血细胞。此外，ELTD1的过表达进一步证实了这一结论。从机制上讲，我们通过生物信息学分析和功能研究证明ELTD1通过Wnt信号通路发挥其功能。此外，我们的结果证明了ELTD1与HPIP之间存在蛋白质-蛋白质相互作用，并进一步揭示HPIP通过LEF1调节Wnt信号通路。总的来说，这些发现表明ELTD1-HPIP-LEF1-Wnt调控轴是hESCs早期造血分化过程中调节HEPs生成的一种新机制，为人类造血的分子机制提供了新的见解。
