ELTD1 inhibits differentiation of hemogenic endothelium progenitors from human embryonic stem cells through the HPIP–Wnt pathway

TL;DR

This study shows that ELTD1 inhibits the formation of blood cell precursors from human embryonic stem cells by affecting the Wnt signaling pathway, offering new insights for regenerative medicine.

Contribution

The discovery of the ELTD1–HPIP–LEF1–Wnt regulatory axis as a novel mechanism controlling hemogenic endothelium progenitor generation from hESCs.

Findings

ELTD1 expression is highly correlated with hemogenic endothelium progenitor specification from hESCs.

Knockdown of ELTD1 increases hemogenic endothelium progenitors and hematopoietic cell production.

ELTD1 functions through the Wnt pathway via interaction with HPIP and LEF1.

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.

Hematopoietic stem cell (HSC) transplantation is used to treat blood cancers but faces challenges such as donor shortages and complications. Researchers are exploring human embryonic stem cells (hESCs) as an alternative source for these stem cells. In this study, researchers focused on a protein called ELTD1, which may play a role in forming hemogenic endothelium progenitors (HEPs), a key step in creating hematopoietic stem cells. They used genetic techniques to study ELTD1’s function in hESCs. By reducing ELTD1, they found an increase in HEPs and subsequent blood cell production. This suggests that ELTD1 negatively regulates early blood cell development by affecting the Wnt signaling pathway, a crucial communication system in cells. The study concludes that targeting ELTD1 could improve the generation of blood cells from hESCs, offering potential advancements in regenerative medicine.

This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

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