Editor's Note: In 2025, the highly anticipated 30th European Hematology Association (EHA) Annual Congress was grandly held in Milan, Italy. This conference brought together top experts and scholars from around the world to discuss cutting-edge topics in basic research and clinical translation in the field of hematology. Professor Sten Eirik Jacobsen of the Karolinska Institutet, Sweden, and the University of Oxford, UK, was invited to deliver a keynote speech titled "Heterogeneity of Hematopoietic Stem Cells: What Really Is a Stem Cell?" His team's breakthrough research offers a disruptive new perspective on our understanding of the fundamental composition of the hematopoietic system and the origin of hematologic malignancies.The human hematopoietic system is responsible for vital functions of substance transport and immune defense, with an astonishing cell turnover rate—approximately 90% of all cells are replaced daily by the hematopoietic system. The source of this vast and intricate biological factory is the rare yet powerful hematopoietic stem cells (HSCs). For over sixty years, the classical model established by Till and McCulloch has been the cornerstone of hematology. This model posits that HSCs are “omnipotent” cells at the apex of the hematopoietic hierarchy, possessing multipotent differentiation potential and self-renewal capabilities, capable of producing all blood cell lineages in a balanced manner. However, with the advancement of research technologies, this classical model is facing new challenges. Professor Sten Eirik Jacobsen’s presentation centered on his team’s series of pioneering work on the heterogeneity of hematopoietic stem cells. His research not only confirms the existence of lineage-biased stem cells but also reveals their unique regulatory mechanisms and stability throughout life, prompting profound reflection within the academic community on the fundamental question: “What really is a stem cell?”
Breaking with Tradition: Mouse Models Reveal the Stable Existence of Lineage-Biased Stem Cells
To investigate the true behavior of single stem cells in vivo, Professor Jacobsen’s team employed a classic experimental technique—single-cell transplantation. Researchers transplanted a single HSC into a recipient mouse whose own hematopoietic system had been ablated. By amplifying the contribution of a single stem cell, they could observe its long-term lineage reconstitution patterns. Professor Jacobsen emphasized, “Although this method is artificial, it allows us to observe the intrinsic potential and fate decisions of a single stem cell with extremely high resolution.”
Through long-term tracking of thousands of single-cell transplanted mice, the team made a surprising discovery: the patterns of hematopoietic reconstitution were not uniform. Instead, they consistently presented as five distinct types, with four being more common. In addition to the classic “multipotent stem cells” that can balancedly reconstitute all blood lineages, there were also “unilineage-restricted stem cells” that only generate platelets, as well as restricted stem cells lacking either T cells or both B and T cells. Professor Jacobsen specifically noted, “These lineage-biased stem cells are already present in young adult mice and are not a product of aging, which indicates they are an inherent component of the hematopoietic system.”
More importantly, secondary transplantation experiments confirmed that these properties are intrinsically determined by the stem cells and are heritably stable. For instance, when a stem cell that only produces platelets was re-transplanted into a new recipient mouse, it continued to generate only platelets. This powerfully demonstrates its robust self-renewal capacity and highly stable lineage commitment. Interestingly, although these cells exhibit strict lineage restriction in vivo, they retain the potential to differentiate into other lineages under in vitro culture conditions when specific inducing factors are applied. Professor Jacobsen concluded, “We believe these cells are multipotent stem cells that are ‘committed’ to platelet regeneration. They possess the potential for multilineage differentiation, but their fate is firmly locked under physiological conditions.”
The “Dual-Track System” of Platelet Production: Two Independent and Parallel Stem Cell Pathways
Based on these findings, a deeper question emerged: How do these different types of stem cells produce platelets? Do they use the same downstream progenitor pathways? Professor Jacobsen’s team’s research revealed an exciting “dual-track” model.
The study found that classic multipotent stem cells follow the traditional, hierarchical pathway of stepwise differentiation, passing through a series of intermediate stages such as short-term stem cells and multipotent progenitors, to ultimately generate megakaryocyte progenitors and platelets. In contrast, the platelet-restricted stem cells take a “shortcut,” directly differentiating into megakaryocyte progenitors with almost no detectable intermediate progenitors.
To validate this “dual-track” hypothesis, the team utilized a key molecular marker—Flt3 (Fms-like tyrosine kinase 3). Flt3 is specifically expressed in multipotent progenitors. By constructing an Flt3-Cre reporter mouse model, the researchers could precisely trace Flt3-positive cells and all their descendants. The results showed that all blood cells produced by multipotent stem cells, including platelets, were positive for the Flt3 reporter gene. Surprisingly, the platelets produced by the platelet-restricted stem cells were completely negative for the Flt3 reporter gene. “This result clearly demonstrates that the two pathways are completely independent,” Professor Jacobsen explained. “One is the classic pathway that goes through an Flt3-positive stage, and the other is a ‘shortcut’ pathway that completely bypasses the Flt3 expression stage.” In steady-state hematopoiesis in young mice, the classic pathway is the main contributor to platelet production. However, under certain stress conditions, such as after clearing all progenitor cells with drugs, the shortcut pathway is rapidly activated to quickly replenish platelets. Furthermore, the use of this shortcut pathway increases significantly with age, suggesting it may play an important role in age-related hematopoietic changes.
From Animals to Humans: Clonal Hematopoiesis Research Confirms the Long-Term Stability of Lineage Fate
To verify the applicability of these findings in humans, the Jacobsen team turned to the phenomenon of “Clonal Hematopoiesis.” With age, certain hematopoietic stem cells in the human body acquire driver mutations and form dominant clones. These mutations act as natural “barcodes,” providing an excellent opportunity to track the long-term fate of single stem cells.
Through deep sequencing and phylogenetic tree analysis of bone marrow samples from elderly healthy donors, the research team was able to trace the origin and evolutionary history of these clones. The data presented by Professor Jacobsen was compelling: “We found that in elderly human individuals, there exist stem cell lineage restriction patterns that are highly consistent with those in the mouse models, including multipotent, T-cell-deficient, and B/T-cell-deficient types.” Even more persuasive was the evidence from prospective studies. The team conducted continuous tracking of specific stem cell clones for up to five years, and the results showed that the lineage output of these clones exhibited extremely high stability. “We tracked 25 different clones, and whether they were multipotent or restricted, their behavioral patterns remained almost unchanged over five years. A restricted clone will remain restricted.” This finding not only confirms the intrinsic determination and long-term stability of stem cell lineage fate but also provides important clues for understanding the evolution of myeloid malignancies, as these cancers originate from mutated hematopoietic stem cells that can persist for a lifetime.
Expert Perspective: How Should We Redefine “Stem Cell”?
At the end of his presentation, Professor Jacobsen posed a profound question to all attendees: “Based on these findings, how should we define a ‘stem cell’?” The traditional definition includes three core elements: being at the apex of the hierarchy, possessing multipotency, and having extensive self-renewal capacity. However, the newly discovered lineage-restricted stem cells clearly challenge this definition. They undoubtedly possess the most central feature of a stem cell—lifelong self-renewal capacity—which distinguishes them from all progenitors with a limited lifespan. They are multipotent in potential but highly specialized in physiological function. They may not reside at the “apex” of the traditional hierarchical model but exist in parallel with the apical cells, collectively maintaining life’s activities.
“These studies indicate that the hematopoietic stem cell population is far more diverse than we previously imagined. Perhaps we should accept a more pluralistic definition of a stem cell, acknowledging the existence of a series of functionally specialized yet equally long-term self-renewing stem cell subsets that work in concert to ensure the stability and efficiency of the hematopoietic system during homeostasis, stress, and aging,” Professor Jacobsen concluded.
This disruptive research not only deepens our understanding of the fundamental laws of life but also points to new directions for the future development of hematology, immunology, and oncology. It shows us that it is this seemingly “imperfect” heterogeneity and complexity that endows biological systems with unparalleled resilience and adaptability. The exploration by Professor Jacobsen’s team perfectly illustrates the charm and value of basic scientific research, inspiring scientists worldwide to continuously challenge the unknown and pursue the truth. Contribution/Interview Source: Oncology Outlook – Oncology Express
