Expression of the Clusterin gene in hematopoietic stem cells marks an age-related shift toward myeloid/platelet over lymphoid cell production
Hematopoietic stem cells (HSCs) can differentiate into any blood cell. However, as HSCs age, they are more likely to differentiate into platelets and myeloid cells. This age-dependent shift is poorly understood due to a lack of marker genes. Now, scientists from the University of Tokyo present the Clusterin (Clu) gene as a novel biomarker of HSC aging. This allows easy identification of aged HSCs, shedding light on the biological mechanisms of aging.
In recent years, there has been a growing trend of an aging patient population and an increasing prevalence of age-associated diseases, underscoring the need for advancing research into the biological mechanisms of aging. Of particular scientific interest are hematopoietic stem cells (HSCs), which undergo profound age-related phenotypic and functional transformations.
HSCs, found in bone marrow, have the capacity to differentiate into various blood cell types, including red blood cells, different white blood cells, and platelets. However, with age, HSCs become biased toward differentiating into myeloid cells and platelets rather than lymphocytes. This myeloid/platelet-biased differentiation disrupts normal blood cell production (hematopoiesis) and can contribute to anemia, immune deficiencies, and even blood cancers.
Many studies have explored ways in which aged HSCs can be rejuvenated. These methods are only partially effective because the exact mechanics of HSC aging remain unknown. The lack of ‘reporter systems,’ genes that can visually mark aged HSCs makes it difficult to identify aged HSCs within the HSC population and is a major reason why the aging process is hard to study. The discovery of an effective marker/reporter gene for aged HSCs can clear the initial barriers to understanding HSC aging.
In a groundbreaking study published in the journal Blood on March 25, 2025, a research team from the Institute of Medical Science, The University of Tokyo, led by Professor Atsushi Iwama and Project Assistant Professor Shuhei Koide, has uncovered a significant breakthrough in understanding HSC aging. Through single-cell RNA-sequence analysis comparing young mice (8–10 weeks old) with aged mice (18–20 months old), the researchers identified Clusterin (Clu), a molecular chaperone, as a novel marker capable of functionally categorizing aged HSCs.
“Our study used Clu-GFP transgenic reporter mice as a model,” Dr. Koide explained. “The expression of Clu also drives the expression of green fluorescent protein (GFP), which acts as a reporter gene and glows green in flow cytometry. This allowed easy identification of aged HSCs and is a more efficient approach than previous studies on other biomarkers, which used antibodies to visualize the marker protein.”
Clu-positive (Clu+) HSCs were found to be a minor population in mice fetuses and expanded with age, explaining the gene’s association with HSC aging. Clu+ HSCs showed an increased propensity towards differentiating into platelets or myeloid cells. In the bone marrow, Clu+ HSCs preferred self-renewal over differentiating into other cell types. In contrast, Clu-negative (Clu–) HSCs showed no bias in differentiation and maintained a balanced cell production approach typical of younger stages. During development, the differentiation of stem cells is crucial, as various tissue and organ formations depend on it. As expected, Clu– HSCs were the majority of the HSC population during fetal development, but the subset progressively becomes a minority as the animal ages. While both HSC subsets retain long-term self-renewal abilities, they contribute differently to blood cell production. The increasing prevalence of Clu+ HSCs drives age-related changes in the stem cell population, while Clu– HSCs maintain more youthful characteristics. These shifting proportions between Clu+ and Clu– HSCs fundamentally define the aging process of HSCs.
“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.”
Clu-GFP mice enable tracking of aged hematopoietic stem cells (HSCs). The increasing abundance of Clu+ HSCs drives age-related changes in the stem cell population, while Clu– HSCs maintain more youthful characteristics. The changing balance between Clu+ and Clu– HSCs drives the core aging process in HSCs.
Reference
Journal：Blood
Title of original paper：
Tracking clusterin expression in hematopoietic stem cells reveals their heterogeneous composition across the lifespan
DOI：
10.1182/blood.2024025776
Authors：
Shuhei Koide1, Motohiko Oshima1, Takahiro Kamiya1, Zhiqian Zheng1, Zhaoyi Liu1, Ola Rizq1, Akira Nishiyama2, Koichi Murakami2,3, Yuta Yamada1, Yaeko Nakajima-Takagi1, Bahityar Rahmutulla4, Atsushi Kaneda4,5, Kazuaki Yokoyama6, Nozomi Yusa7, Seiya Imoto8, Fumihito Miura9, Takashi Ito9, Tomohiko Tamura2,3, Claus Nerlov10, Masayuki Yamashita1,11, and Atsushi Iwama1,12,13
Affiliations：
1Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
2Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
3Advanced Medical Research Center, Yokohama City University, Yokohama, Japan
4Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
5Health and Disease Omics Center, Chiba University, Chiba, Japan
6 Department of Hematology/Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
7 Department of Laboratory Medicine, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
8 Division of Health Medical Intelligence, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
9 Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
10 MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
11 Division of Experimental Hematology, Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
12 Laboratory of Cellular and Molecular Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
13 The University of Tokyo Pandemic Preparedness, Infection and Advanced Research Center (UTOPIA), The University of Tokyo, Tokyo, Japan
About The Institute of Medical Science, The University of Tokyo
The Institute of Medical Science, The University of Tokyo (IMSUT), established in 1892 as the Institute of Infectious Diseases and renamed IMSUT in 1967, is a leading research institution with a rich history spanning over 127 years. It focuses on exploring biological phenomena and disease principles to develop innovative strategies for disease prevention and treatment. IMSUT fosters a collaborative, interdisciplinary research environment and is known for its work in genomic medicine, regenerative medicine, and advanced medical approaches like gene therapy and AI in healthcare. It operates core research departments and numerous specialized centers, including the Human Genome Center and the Advanced Clinical Research Center, and is recognized as Japan’s only International Joint Usage/Research Center in life sciences.About Professor Atsushi Iwama from the Institute of Medical Science, The University of Tokyo
Atsushi Iwama is a Professor in the Division of Stem Cell and Molecular Medicine at The Institute of Medical Science, The University of Tokyo, Japan. He is a medical doctor who graduated from Niigata University, Japan. After more than five years of medical practice, he obtained a PhD from Kumamoto University, Japan, in 1996. Dr. Iwama’s research group studies stem cell biology, epigenetics, and hematology, specifically in relation to the mechanisms of stem cell aging and self-renewal in blood. Currently, Dr. Iwama’s lab is focused on aging of hematopoietic stem cells and aged-associated hematological malignancies.Funding information
This work was supported in part by Grants-in-Aid for Scientific Research (26115002, 19H05653, 19H05746, 24H00066 to AI, 22K16298 to SK, 22H03101 to MY) and Promotion of Distinctive Joint Usage/Research Center Support Program Grant (JPMXP0618217493 to AI) at the Advanced Medical Research Center, Yokohama City University from MEXT/JSPS, Japan. Funding was also provided from AMED, Japan (21zf0127003h0001, 243fa627001 to AI, 23jm0610094h0001 to SK), and Grants-in-Aid from Uehara Memorial Foundation, Japanese Society of Hematology, and SENSHIN Medical Research Foundation (SK).Media contact
Affiliation: Project Coordination Office, The Institute of Medical Science, The University of Tokyohttps://www.ims.u-tokyo.ac.jp/