Clusterin(g) and decoding HSC aging Free

Hematopoietic stem cells (HSCs) undergo profound changes over an organism’s life span, but tracking these age-related transitions has remained a challenge. In this issue of Blood, Koide et al¹ make a compelling contribution by identifying clusterin (Clu) as a novel marker that delineates functionally distinct HSC subsets throughout life. By leveraging Clu-GFP reporter mice, the authors track the molecular and functional evolution of the HSC population across aging.

Aging skews hematopoiesis toward myeloid and platelet lineages while reducing lymphoid output, potentially contributing to immune dysfunction and hematologic disease.² Koide et al now demonstrate that Clu expression reliably marks a subset of myeloid/platelet-biased HSCs that expand with age. A breakthrough of this study lies in the use of Clu-GFP reporter mice, which reveal that Clu-positive (Clu⁺) HSCs emerge as a minor subset during fetal development and progressively expand with age. Transplantation and culture assays show that these Clu⁺ HSCs favor self-renewal over differentiation and exhibit functional skewing toward the myeloid and platelet lineages. In contrast, Clu-negative (Clu^–) HSC remain constant and maintain youthful characteristics, including a balanced output upon transplantation and a gene expression profile reminiscent of young HSCs. This suggests that the age-related expansion of Clu⁺ HSCs accounts for many of the functional and molecular changes associated with HSC aging, whereas Clu^– HSCs persist as a reservoir of young-like stem cells.

Importantly, Clu⁺ HSCs partially overlap with previously described subsets of myeloid/platelet-biased HSCs identified by CD150,³ CD41,⁴ von Willebrand factor,⁵ or P-selectin⁶ expression. However, whether Clu⁺ HSCs represent a distinct subset with unique epigenetic and transcriptomic properties remains to be determined.

One of the most striking findings by Koide et al is that Clu⁺ HSCs expand dramatically with age, whereas Clu^– HSCs maintain a stable population size. This suggests that HSC expansion during aging is not uniform but rather a biased process favoring self-renewing, myeloid/platelet-biased subsets. The mechanisms driving this selective expansion remain unclear. Do Clu⁺ HSCs have an intrinsic propensity toward increased self-renewal, or do they gain a selective advantage in the aged bone marrow niche? A closely linked question is the developmental origin of Clu⁺ and Clu^– HSCs. Is one HSC subset derived from the other, or do these populations exist in parallel throughout life? The transplantation experiments performed by Koide et al suggest some plasticity between these subsets, as Clu^– donor HSCs can give rise to Clu⁺ HSCs in recipient mice. However, the reverse also occurs: Clu⁺ donor HSCs can robustly generate Clu^– HSCs. This phenotypic plasticity suggests that interconversion between these states may occur at least upon transplantation. Future studies employing fate-mapping approaches could clarify the developmental relationship between Clu⁺ and Clu^– HSCs.

Aged Clu^– HSCs retain youthful transcriptional and epigenetic signatures, as well as balanced transplantation potential, but they may be functionally marginalized by the numerical expansion of Clu⁺ HSCs. A closer look at the data from Koide et al reveals that aged Clu^– HSCs still exhibit transcriptional changes as well as a decline in repopulation potential compared to their young counterparts, suggesting that aging-associated alterations may be more subtle but still present. Future studies comparing the molecular properties and function of young and aged HSCs, separated by Clu expression, will be essential to determine whether Clu^– HSCs truly escape the effects of aging. However, recent findings that selective depletion of platelet/myeloid-biased HSCs in aging mice resulted in considerable hematopoietic and immunological rejuvenation⁷ argue that Clu^– HSCs may indeed resist aging, whereas accumulated Clu⁺ HSC exert detrimental effects.

Clu is regarded a chaperone involved in protein homeostasis, apoptosis, and cellular stress responses. However, its role in hematopoiesis and HSC biology remains unclear. Notably, Clu is highly expressed in megakaryocytes and platelets, placing it among known megakaryocytic markers of HSC subsets that expand in aged mice. Recent studies have identified 2 pathways of thrombopoiesis: a short route in which HSCs directly give rise to megakaryocyte progeny, and a longer route through canonical multipotent progenitors.^8,9 These pathways generate functionally heterogeneous megakaryocyte progenitors that can be distinguished by CD48 expression. Interestingly, Clu-GFP expression selectively labels megakaryocyte progenitors, which are direct progeny of HSCs. Increased direct differentiation of the enlarged pool of platelet/myeloid-biased HSCs toward the megakaryocytic lineage has been reported to drive the elevated production of hyperreactive platelets in aging mice.¹⁰ Therefore, it will be interesting to explore whether reducing the expansion of platelet/myeloid-biased HSCs decreases thrombotic events in older patients.

Koide et al provide a framework for studying HSC aging, with implications for regenerative medicine and age-related hematologic disorders. By establishing Clu as a functional marker of HSC heterogeneity, this study lays the groundwork for future research aimed at preserving hematopoietic health across the life span.

Conflict-of-interest disclosure: A.G. declares no competing financial interests.