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Discovery of Molecular Switch Enhances Blood Stem Cell Regeneration Potential

A groundbreaking study led by investigators at Weill Cornell Medicine has uncovered the pivotal role of a single molecular switch in enabling blood stem cells to transition into an activated and regenerative state, crucial for their capacity to generate new blood cells. This finding holds the promise of enhancing the effectiveness of bone marrow transplants and gene therapies.

Stem cells are specialized cells with the remarkable ability to rejuvenate various tissues in the body. Typically, they remain in a dormant state, characterized by slow division. However, in response to injury, these cells can activate and proliferate quickly, maturing into fully functional cells to aid in tissue repair.

In research published on February 25 in Nature Immunology, the team identified a DNA transcription-regulating protein known as FLI-1 as a key player in the regenerative process of blood stem cells. These cells mainly reside in the bone marrow until they are prompted to “mobilize” and enter the bloodstream. The researchers demonstrated that by temporarily introducing FLI-1 into dormant adult mobilized bone marrow stem cells, they can spur these cells into action, significantly enhancing their self-expansion and improving their chances of successful transplantation into recipients.

“Our findings could greatly enhance the efficacy of marrow transplants and gene therapies targeting marrow cells, especially in scenarios where the donor has a limited supply of healthy blood stem cells,” remarked Dr. Shahin Rafii, the study’s senior author. Dr. Rafii holds prestigious positions, including director of the Hartman Institute for Therapeutic Organ Regeneration and chief of the division of regenerative medicine at Weill Cornell Medicine.

Bone marrow transplants, which incorporate blood stem cells, are vital for replenishing the populations of blood and immune cells in patients, especially in cancer treatments. In certain cases, physicians utilize healthy blood stem cells obtained from patients themselves, though these might be more challenging to activate and amplify after chemotherapy or radiation treatments. Gene therapies aimed at blood disorders such as beta-thalassemia similarly rely on harvesting patients’ blood stem cells, inserting therapeutic genes, and then expanding these vulnerable cells before they are reintroduced to the patient. All these therapeutic strategies would benefit from a reliable means to promote a regenerative state in quiescent blood stem cells.

To examine the regenerative capabilities, the researchers employed single-cell profiling and other methodologies to assess the variances in gene expression between quiet and activated blood stem cells. Their exploration led to the focus on FLI-1, a transcription factor that regulates thousands of genes. They found that in the absence of FLI-1, blood stem cells remain inactive and disengaged from interactions with their surrounding microenvironment, especially endothelial cells that form blood vessels. FLI-1 re-establishes these connections and promotes a regenerative state in stem cells, substantially enhancing their ability to proliferate and replenish the blood cell supply in a new host.

While mutations that result in excessive FLI-1 activity have been linked to certain leukemias, the research team devised a method to stimulate blood stem cells with FLI-1 for limited periods, akin to the approach used in modified mRNA-based vaccines.

“The stem cells we activate with FLI-1 modified mRNA emerge from their dormant state, proliferate, and integrate functionally within the host without signs of malignancy,” explained Dr. Tomer Itkin, a co-first author of the study and currently the director of Tel Aviv University’s Neufeld Cardiovascular Research Institute.

The study also shed light on a long-standing question in the field of blood stem cells, revealing that the heightened regenerative capacity of blood stem cells derived from human umbilical cords—compared to those from adults—is linked to variations in FLI-1 activity, which enhances their ability to interact with a regenerative vascular niche.

In conducting their research, the team engaged in extensive computational analyses to clarify the role of FLI-1 in stem cell activation and its interplay with established signaling pathways governing stem cell self-renewal and survival. They also elucidated the relationship between blood stem cells and their bone marrow environment.

“Our results indicate that stem cell activity is interdependent; it is shaped not only by signals from the endothelial cell vascular niche but also by the responsiveness between these cells and their environment,” noted co-first author Sean Houghton, who served as a bioinformatics analyst during the study.

The research team aims to further develop their modified mRNA-based approach to transiently introduce FLI-1 into blood stem cells, with plans to eventually test this method in human clinical trials. If successful, their strategy could pave the way for innovative treatments for a wide array of blood disorders, facilitating stable and safe long-term blood production.

Dr. Shahin Rafii is a co-founder of Angiocrine Bioscience without any financial compensation.

This research was supported by grants from the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Institute of Allergy and Infectious Diseases, among others, through various grant numbers, as well as support from the Hartman Institute for Therapeutic Organ Regeneration, the Ansary Stem Cell Institute, and the Selma and Lawrence Ruben Daedalus Fund for Innovation at Weill Cornell Medicine.

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