This article highlights research in the paper by one of the finalists of the Inspiring Science Awards 2025. The finalist is Anu P V, also the first author of the paper.

How do our blood cells first form? Researchers from IISER Thiruvananthapuram (IISER TVM) have given the first detailed experimental demonstration of a new player in controlling a major phase in vertebrate embryo development. In a developing embryo, endothelial cells— cells that line the blood vessels, lymphatic vessels and the heart — transform into hematopoietic cells that give rise to all the blood cells in the body.

For a long time, it was known that this transition, called the endothelial-to-hematopoietic transition (EHT) was controlled by signaling molecules. Recently, in a study reported in Science Advances, researchers have demonstrated that the EHT is also driven by a switch in the metabolic pathway.

During development, the hematopoietic stem cells (HSCs) appear in the aorta-gonad-mesonephros (AGM) region of the embryo, from where they first migrate to the fetal liver, and eventually to the bone marrow, where they reside for the entire adult life. The EHT that forms the HSCs is an evolutionarily conserved process in which endothelial cells first transition into hemogenic endothelium and then into hematopoietic cells.

Researchers showed that endothelial cells in mouse embryos undergoing glycolysis switch their metabolism to oxidative phosphorylation as they transition to hematopoietic cells. Glycolysis and oxidative phosphorylation are both metabolic pathways required for energy production. The two pathways significantly differ in various aspects such as location in the cell, amount of ATP generated, and starting and end products. Importantly, oxidative phosphorylation is more efficient in terms of energy production compared to glycolysis.

Researchers showed that the metabolic switch happens exactly when the endothelial cells are transitioning into hematopoietic stem cells. They further observed that it is essential for the endothelial cells to retain their glycolytic state, without which fewer hematopoietic stem cells are formed. On the other hand, stabilisation of proteins such as hypoxia-inducible factor- 1 alpha (HIF-1α) that promote glycolysis leads to increased appearance of hematopoietic clusters in the AGM.

Since glycolysis takes place in the cytoplasm, and oxidative phosphorylation occurs in the mitochondrial inner membrane, researchers expected endothelial cells to show lower mitochondrial content. However, they observed just the opposite— a higher mitochondrial content in endothelial cells. With respect to activity though, the hematopoietic cells showed higher mitochondrial activity. “We found something exciting! The hematopoietic cells had more active mitochondria and generated more reactive oxygen species (ROS). Meanwhile, the endothelial cells were taking in more glucose, had more of the glucose transporter GLUT1, and were using glucose for energy through glycolysis. What’s truly interesting is that this high glycolytic metabolic state in the endothelial cells actually helps kick-start the formation of blood stem cells”, explains Anu P V, a PhD student at IISER TVM, and the first author of the paper.

The study highlights the fact that the metabolic status of stem cells determines their properties and functions. It was previously known that stem cells in the fetal liver undergo rapid proliferation and generate energy through oxidative phosphorylation. However, once they reach the bone marrow as adult stem cells, they remain quiescent and utilise glycolysis for energy.

Hematopoietic stem cells from the bone marrow are used in cancer treatment to restore the cells damaged during chemotherapy or radiation therapy. However, maintaining stem cells in their quiescent state and their expansion remains a challenge, as they have a tendency to differentiate. The recent study highlights the significance of the glycolytic pathway in retaining the stemness of stem cells, eventually improving their potential in cancer treatment. “If stem cells can be maintained in vitro by providing glycolytic and hypoxic conditions, they can be used for treatment”, says Anu P V.

He adds that in the future, the study can be extended to explore how maternal metabolic disorders such as gestational diabetes affect early hematopoiesis. The study suggests that controlling oxygen sensing and metabolic pathways could enable expansion of hematopoietic stem cells in vivo, and provide novel therapeutic approaches to treat blood cancers.