Stem cells are immature cells that have a basic regenerative role in virtually all tissues. They normally exist in a quiescent, slowly dividing state, but after an injury can replace tissue by switching to an activated state in which they multiply rapidly and turn into mature, functional cells. According to a new preclinical study led by Weill Cornell Medicine scientists, a single molecular switch is essential for blood stem cells to enter an activated, regenerative state in which they produce new blood cells. The discovery could lead to more effective bone marrow transplants and gene therapies. The researchers, found that a DNA transcription factor called FLI-1 has a critical role in this regenerative process for blood stem cells, which are mostly resident in the bone marrow until they are stimulated or “mobilized” to move into the bloodstream.
They showed that transiently producing FLI-1 in quiescent adult mobilized bone marrow stem cells activates them so that they swiftly expand their numbers and have a better chance of being transplanted successfully into a new host. Marrow transplants allow the replenishment of the blood cell and immune cell populations in recipients, and are important elements in the treatment of some cancers. Doctors also sometimes replenish blood cells in cancer patients using healthy blood stem cells purified from the patients themselves. Similarly gene therapies, like for beta-thalassemia, require the stem cells harvesting from patients’ blood, insertion of a therapeutic gene and their expansion of in lab before re-infusion. All these applications would be improved if doctors had a safe, reliable method for switching quiescent blood stem cells into a more regenerative state.
The study involved extensive computational analysis to decipher the role of FLI-1 in stem cell activation and its integration with known signaling pathways that drive stem cell self-renewal and survival. It also clarified the relationship between blood stem cells and their marrow environment, specifically the vascular niche. In the study, the researchers used single-cell profiling and other techniques to analyze differences in gene activity between quiescent and activated blood stem cells. Eventually they zeroed in on FLI-1, a transcription factor protein that can control the activity of thousands of genes. Its absence, they showed, keeps blood stem cells quiescent, and largely shuts down these cells’ interactions with surrounding marrow cells, in particular the specialized endothelial cells that compose the blood vessels.
FLI-1’s activity, in contrast, restores stem cells’ connections and co-adaptability with their microenvironmental endothelial cell niche, also known as the vascular niche. FLI-1 pushes them into an activated, regenerative state—greatly improving their ability to expand and restore the blood cell supply in a new host. FLI-1 mutations are known drivers of some leukemias; however, scientists developed a method for stimulating blood stem cells with FLI-1 for only a few days at a time. The team also addressed a long-standing puzzle in the blood stem cell field by showing that the greater regenerative potential of human umbilical cord-derived blood stem cells, compared with adult stem cells isolated from blood, is associated with differences in these cells’ levels of FLI-1 activity, affecting their potency to interact with a regenerative vascular niche.
FLI-1 has been defined by Schutt et al. (2022) as a “druggable” transcription factor in the context of T cell response in graft-versus-host disease (GVHD). Chemotherapeutics like irinotecan and etoposide were found to be inhibitors of its function. In this context, however, an activating molecule whould be instead desirable to enhance its function to allow stem cell expansion. The researchers plan to follow up with further preclinical development and scaling up of their modified mRNA-based method to transiently introduce FLI-1 in the blood stem cells, with the ultimate goal of testing it in human patients. Their approach could set the stage for treating wide range of blood disorders with long-term stable and safe blood production.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Itkin T et al. Nat Immunol. 2025; 26(3):378-390.
Wu Q, Zhang J et al. Nature 2024; 627:839–846.
Schutt SD et al. J Clin Invest. 2022; 132(21):e143950.
