Aging is associated with functional and molecular changes in distinct hematopoietic stem cell subsets

• Published in: Nature communications 2024-09, Vol.15 (1), p.7966-16, Article 7966
• Main Authors: Su, Tsu-Yi, Hauenstein, Julia, Somuncular, Ece, Dumral, Özge, Leonard, Elory, Gustafsson, Charlotte, Tzortzis, Efthymios, Forlani, Aurora, Johansson, Anne-Sofie, Qian, Hong, Månsson, Robert, Luc, Sidinh
• Format: Article
• Language: English
• Subjects: 13; 13/106; 13/31; 38; 38/39; 38/91; 45; 49; 631/532/1542; 631/532/2441; 631/532/7; 64; 64/60; Adaptive immunity; Adaptive systems; Aging; Aging - genetics; Aging - physiology; Animals; Cell Differentiation; Cell Lineage - genetics; Female; Gene expression; Gene Expression Regulation; Hematopoiesis; Hematopoiesis - genetics; Hematopoietic stem cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Hematopoietic system; Hemopoiesis; Heterogeneity; Humanities and Social Sciences; Male; Malignancy; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Molecular properties; multidisciplinary; Myeloid Cells - cytology; Myeloid Cells - metabolism; Myelopoiesis; Regulatory mechanisms (biology); Risk factors; Science; Science (multidisciplinary); Stem cells
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-52318-1

Age is a risk factor for hematologic malignancies. Attributes of the aging hematopoietic system include increased myelopoiesis, impaired adaptive immunity, and a functional decline of the hematopoietic stem cells (HSCs) that maintain hematopoiesis. Changes in the composition of diverse HSC subsets have been suggested to be responsible for age-related alterations, however, the underlying regulatory mechanisms are incompletely understood in the context of HSC heterogeneity. In this study, we investigated how distinct HSC subsets, separated by CD49b, functionally and molecularly change their behavior with age. We demonstrate that the lineage differentiation of both lymphoid-biased and myeloid-biased HSC subsets progressively shifts to a higher myeloid cellular output during aging. In parallel, we show that HSCs selectively undergo age-dependent gene expression and gene regulatory changes in a progressive manner, which is initiated already in the juvenile stage. Overall, our studies suggest that aging intrinsically alters both cellular and molecular properties of HSCs. Aging is a risk factor for blood malignancies, leading to increased myelopoiesis and impaired immunity. Here, the authors show that aging alters cellular and molecular properties of HSC subsets, with changes starting as early as the juvenile stage.