New Study Reveals That FLI-1 Can Activate Quiescent Hematopoietic Stem Cells

Stem cells are immature cells that have a fundamental regenerative role in almost all tissues. They are usually in a quiescent, slowly dividing state. But after injury, they can repair damaged tissues by switching to an activated state so that they can rapidly proliferate and become mature, functional cells. For example, hematopoietic stem cells mostly reside in the bone marrow and remain quiescent until they are stimulated or "mobilized" into the blood.

A preclinical study led by researchers at Weill Cornell Medical College and published in the journal Nature Immunology found that a DNA transcription regulator protein called FLI-1 plays a critical role in the regeneration of hematopoietic stem cells. They pointed out that the brief production of FLI-1 in quiescent adult hematopoietic stem cells in the bone marrow after mobilization activates them, allowing them to rapidly expand in number and have a better chance of successfully engrafting into a new host. This discovery may lead to more effective bone marrow transplants and gene therapies.

"The approach we outline in this study could greatly improve the efficiency of bone marrow transplants and gene therapies that target bone marrow cells, especially when a donor has a very limited supply of viable blood stem cells," said senior author Shahin Rafii, PhD, professor of genetic medicine at Weill Cornell Medicine.

Bone marrow transplants involving blood stem cells replenish the recipient's blood and immune cell populations and are an important factor in treating certain cancers. Doctors sometimes also use healthy blood stem cells extracted from cancer patients to replenish a patient's blood cells. Although if these stem cells have been treated with chemotherapy and/or radiation, they may be more difficult to activate and expand.

Similarly, some gene therapies, particularly for blood disorders such as beta thalassemia, require harvesting a patient's blood stem cells, inserting a therapeutic gene, and expanding these genetically modified blood stem cells in the lab before infusing them into the patient. All of these applications would be improved if doctors had a safe and reliable way to convert quiescent blood stem cells into a more regenerative state.

In this study, the researchers used single-cell analysis and other techniques to analyze the differences in gene activity between quiescent and activated hematopoietic stem cells. Ultimately, they zeroed in on FLI-1, a transcription factor protein that controls the activity of thousands of genes. They found that its absence kept hematopoietic stem cells quiescent and largely shut down the cells' interactions with surrounding bone marrow cells, particularly the endothelial cells that make up blood vessels.

In contrast, FLI-1 activity restored hematopoietic stem cells' connection and coadaptation with the endothelial cell niches (also called vascular niches) in their microenvironment. FLI-1 pushes them into an activated, regenerative state, greatly improving their ability to expand and restore blood cell supply in a new host.

Figure 1. Hematopoietic Fli-1 deficiency leads to thrombocytopenia and failure of hematopoietic stem cell regeneration. (Itkin T, et al., 2025)

Mutations that drive FLI-1 overactivity are known drivers of some leukemias. However, the researchers developed a way to stimulate hematopoietic stem cells with FLI-1 for just a few days at a time, using an approach similar to modified mRNA-based vaccines.

"The hematopoietic stem cells that we activated in this way with FLI-1-modified mRNA woke from dormancy, expanded, and engrafted functionally and durably in transplant recipients without any evidence of cancer," said Dr. Tomer Itkin, co-first author of the paper.

The team also solved a long-standing puzzle in the hematopoietic stem cell field, showing that human umbilical cord-derived hematopoietic stem cells have greater regenerative potential than adult hematopoietic stem cells isolated from the blood. This was related to differences in the levels of FLI-1 activity in these cells, as this difference affected their ability to interact with regenerative vascular niches.

"We showed that hematopoietic stem cell activity is not autonomous or entirely determined by endothelial cell vascular niche signals, but rather depends on signals and adaptations between the two," said Sean Houghton, co-first author of the paper.

The researchers plan to further preclinical development and expand their modified mRNA-based approach to transiently introduce FLI-1 into hematopoietic stem cells, with the ultimate goal of testing it in human patients. Their findings could lay the foundation for long-term stable and safe blood production to treat a variety of blood diseases.