ELTD1 inhibits differentiation of hemogenic endothelium progenitors from human embryonic stem cells through the HPIP–Wnt pathway
Abstract 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 pro...
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| Format: | Article |
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Nature Publishing Group
2025-06-01
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| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-025-01473-6 |
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| author | Qian Luo Yijin Chen Honghu Li Yan Long Wei Shan Xiangjun Zeng Shuyang Cai Ye Meng Cong Wei Yulin Xu Ruxiu Tie Yi Luo Pengxu Qian Meng Zhang He Huang |
| author_facet | Qian Luo Yijin Chen Honghu Li Yan Long Wei Shan Xiangjun Zeng Shuyang Cai Ye Meng Cong Wei Yulin Xu Ruxiu Tie Yi Luo Pengxu Qian Meng Zhang He Huang |
| author_sort | Qian Luo |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-fd462375d3314560bbd5725dda279577 |
| institution | Kabale University |
| issn | 2092-6413 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Experimental and Molecular Medicine |
| spelling | doaj-art-fd462375d3314560bbd5725dda2795772025-08-20T03:45:19ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132025-06-015761216123110.1038/s12276-025-01473-6ELTD1 inhibits differentiation of hemogenic endothelium progenitors from human embryonic stem cells through the HPIP–Wnt pathwayQian Luo0Yijin Chen1Honghu Li2Yan Long3Wei Shan4Xiangjun Zeng5Shuyang Cai6Ye Meng7Cong Wei8Yulin Xu9Ruxiu Tie10Yi Luo11Pengxu Qian12Meng Zhang13He Huang14Bone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of MedicineBone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of MedicineBone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of MedicineBone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of MedicineBone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of MedicineBone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of MedicineBone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of MedicineBone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of MedicineBone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of MedicineBone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of MedicineBone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of MedicineBone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of MedicineBone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of MedicineBone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of MedicineBone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of MedicineAbstract 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.https://doi.org/10.1038/s12276-025-01473-6 |
| spellingShingle | Qian Luo Yijin Chen Honghu Li Yan Long Wei Shan Xiangjun Zeng Shuyang Cai Ye Meng Cong Wei Yulin Xu Ruxiu Tie Yi Luo Pengxu Qian Meng Zhang He Huang ELTD1 inhibits differentiation of hemogenic endothelium progenitors from human embryonic stem cells through the HPIP–Wnt pathway Experimental and Molecular Medicine |
| title | ELTD1 inhibits differentiation of hemogenic endothelium progenitors from human embryonic stem cells through the HPIP–Wnt pathway |
| title_full | ELTD1 inhibits differentiation of hemogenic endothelium progenitors from human embryonic stem cells through the HPIP–Wnt pathway |
| title_fullStr | ELTD1 inhibits differentiation of hemogenic endothelium progenitors from human embryonic stem cells through the HPIP–Wnt pathway |
| title_full_unstemmed | ELTD1 inhibits differentiation of hemogenic endothelium progenitors from human embryonic stem cells through the HPIP–Wnt pathway |
| title_short | ELTD1 inhibits differentiation of hemogenic endothelium progenitors from human embryonic stem cells through the HPIP–Wnt pathway |
| title_sort | eltd1 inhibits differentiation of hemogenic endothelium progenitors from human embryonic stem cells through the hpip wnt pathway |
| url | https://doi.org/10.1038/s12276-025-01473-6 |
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