In the bone marrow, hematopoietic stem cells (HSCs) produce various blood cell types, but this process changes with age. Scientists from the University of Tokyo identified the Clusterin (Clu) gene as a new marker for aging hematopoietic stem cells (HSCs), helping researchers study how aging affects blood formation.
As HSCs age, they tend to favor the production of myeloid cells and platelets over lymphocytes, disrupting the normal process of blood production, known as hematopoiesis. This imbalance can lead to anemia, immune deficiencies, and blood cancers.
Scientists from the University of Tokyo have identified a key aging marker for hematopoietic stem cells (HSCs), shedding light on how these cells undergo changes over time. Clusterin (Clu), a molecular chaperone, has been identified as an effective reporter gene that can help distinguish aged HSCs within the population.
Led by Professor Atsushi Iwama and Project Assistant Professor Shuhei Koide, the team analyzed single-cell RNA sequences in young (8–10 weeks old) and aged (18–20 months old) mice. Their findings, published in Blood on March 25, 2025, represent a significant step toward understanding hematopoietic stem cell (HSC) aging—a crucial challenge for regenerative medicine.
A new way to reverse cell aging
Researchers utilized Clu-GFP transgenic reporter mice to investigate the aging of hematopoietic stem cells (HSCs). When the Clusterin (Clu) gene was expressed, it triggered the production of green fluorescent protein (GFP), making aged HSCs glow under flow cytometry. This method is more efficient than previous techniques that relied on antibody-based visualization.
Scientists found that Clu-positive (Clu+) HSCs, initially a small population in fetal mice, expanded with age. These cells had a greater tendency to differentiate into platelets and myeloid cells, thereby reinforcing their link to hematopoietic stem cell (HSC) aging.
Clu+ HSCs favored self-renewal in bone marrow over producing diverse blood cells, while Clu-negative (Clu–) HSCs maintained a balanced differentiation typical of earlier stages. Since proper stem cell differentiation is crucial for organ and tissue formation, these findings could enhance our understanding of aging-related blood disorders.
During fetal development, most hematopoietic stem cells (HSCs) are Clu-negative (Clu–), but their numbers decrease with age, while Clu-positive (Clu+) HSCs become more dominant.
Both subsets retain long-term self-renewal but contribute differently to blood cell production. Clu+ HSCs drive age-related changes, favoring myeloid and platelet differentiation, while Clu–HSCs maintain youthful characteristics and balanced cell formation.
This shift in proportions between Clu+ and Clu–HSCs plays a fundamental role in defining stem cell aging.
“Our findings suggest that targeting Clu+ aged HSCs could pave the way for new therapeutic strategies to address aging-related diseases,” says Prof. Iwama, “This new approach enables lifelong tracking of the HSC aging process, offering unprecedented insights into cellular aging mechanisms.”
Journal Reference:
- Shuhei Koide, Motohiko Oshima, Takahiro Kamiya et al. Tracking clusterin expression in hematopoietic stem cells reveals their heterogeneous composition across the lifespan. Blood. DOI: 10.1182/blood.2024025776
