bims-mithem 2026-08-09 papers

Issue of 2026–08–09
four papers selected by
Tim van Tienhoven, Erasmus Medical Center

EMBO J. 2026 Aug 05.

P-selectin delineates conserved functional heterogeneity in early hematopoietic stem cell aging in humans and mice.

Chong Yang, Tong Wang, Yue Chai, Lisha Wang, Yixuan Wang, Weili Wang, Fang Dong, Toshio Suda.

Progressive aging of bone marrow hematopoietic stem cells (HSCs) underlies clonal hematopoiesis and age-associated hematologic disorders. Defining early molecular events driving HSC functional decline is essential for rejuvenation strategies. Here, we identify P-selectin (Selp) as a surface marker that stratifies HSCs into conserved functional and transcriptional states during organismal aging in humans and mice. P-selectin expression increases early during aging and remains elevated in old HSCs. Selphigh-HSCs exhibit increased DNA damage and bias towards megakaryocytic/myeloid lineage fate, whereas Selplow-HSCs maintain metabolic integrity, enhanced antioxidant capacity, and reduced myeloid skewing. Transcriptomic analysis revealed that Selphigh-HSCs adopt megakaryocytic-primed, pro-inflammatory, and oxidative stress programs, while Selplow-HSCs retain lymphoid-associated and redox-balanced signatures consistent with a more preserved stem-cell state. Further ATAC-seq analysis demonstrates distinct chromatin landscapes with Selphigh-HSCs being enriched for inflammatory and platelet-related regulatory elements and CTCF motifs, but Selplow-HSCs displaying accessible ETS-driven networks linked to metabolic fitness and stem cell resilience. Together, these findings uncover conserved heterogeneity during blood stem cell aging and establish P-selectin as an early biomarker and potential therapeutic target to mitigate age-associated hematopoietic decline.

DOI: https://doi.org/10.1038/s44318-026-00887-w

Antioxid Redox Signal. 2026 Aug 05. 15230864261475098

Targeted Restoration of Mitophagy Reinvigorates Aged Hematopoietic Stem Cells.

Jin Liu, Aiwei Wu, Jieyu Ling, Liquan Hong, Mingwei Wang, Xinyi Chen, Jianpin Zhou, Zhenyu Ju, Yue Sheng, Hongguang Xia, Hu Wang.

AIMS: Aging-related functional decline in hematopoietic stem cells (HSCs) is closely associated with mitochondrial dysfunction and impaired mitophagy. This study aimed to investigate whether targeted restoration of mitophagy via the myeloid cell leukemia 1 (MCL-1)/light chain 3A pathway could rejuvenate aged HSCs and improve their regenerative capacity.
RESULTS: We identified MCL-1 as the most highly expressed mitophagy receptor in aged HSCs. Treatment with UMI-77, a selective MCL-1 agonist, significantly enhanced mitophagy, reduced mitochondrial mass, improved mitochondrial membrane potential, and reduced reactive oxygen species levels in aged HSCs both in vitro and in vivo. Single-cell RNA sequencing revealed that UMI-77 upregulated mitophagy-related genes (Sqstm1, Fundc1, Bnip3) and restored stemness signatures in long-term HSCs. Transplantation assays demonstrated that UMI-77-treated aged HSCs exhibited superior hematopoietic reconstitution capacity compared with those from control mice. However, this intervention also increased the proportion of myeloid-biased CD150high HSCs, a hallmark of aging.
CONCLUSION: Targeted mitophagy restoration via MCL-1 activation improves mitochondrial fitness and stemness in aged HSCs but does not reverse myeloid bias. These findings highlight mitophagy enhancement as a viable therapeutic approach, while suggesting combinatorial strategies may be needed to fully restore lineage balance in aging hematopoiesis. Antioxid. Redox Signal. 00, 000-000.

Keywords: MCL-1; UMI-77; aging; hematopoietic stem cells; mitophagy

DOI: https://doi.org/10.1177/15230864261475098

Nat Cell Biol. 2026 Aug 06.

Stromal cell senescence augments haematopoietic cell fitness in clonal haematopoiesis.

Jayna J Mistry, Kira A Young, Anna Navarro Figueredo, Gibran Edun, Alicia G Aguilar-Navarro, Patricia A Colom Díaz, Maria Telpoukhovskaia, Inés Fernández Maestre, Sheng F Cai, Katharina S Götze, Anastasia N Tikhonova, Ross L Levine, Jennifer J Trowbridge.

Microenvironment remodelling impacts tumour growth and metastasis, but whether remodelling promotes pre-malignant clonal fitness remains unknown. Here, using single-cell RNA-sequencing of the bone-marrow microenvironment in a mouse model of DNMT3A-mutant clonal haematopoiesis (CH), we identify mesenchymal stromal cells (MSCs) in a molecular state of cellular senescence. Elevated bone-marrow MSC senescence is also observed in humans with CH driven by several common somatic mutations. MSC senescence is induced by mutant haematopoietic cells in a contact-independent manner through production of soluble factors including TNF-α and IL-6. These cytokines activate a Stat3-driven pathway that is necessary and sufficient for MSC senescence induction. Genetic or pharmacological depletion of senescent non-haematopoietic cells reduces the burden of CH and delays progression to myeloid neoplasia. Our findings show that microenvironment remodelling modifies pre-malignant clonal fitness and identifies disruption of the crosstalk between pre-malignant cells and their niche as a cancer prevention strategy.

DOI: https://doi.org/10.1038/s41556-026-02025-4

Blood. 2026 Aug 06. pii: blood.2026034240. [Epub ahead of print]

Expansion of functional human long-term HSCs through restraining excessive cell cycle activation.

Ex vivo expansion of human hematopoietic stem cells (HSCs) holds promise for overcoming their limited availability, a major barrier to broader clinical application. Although recent advances in culture systems can increase HSC numbers, these conditions frequently impair self-renewal and induce myeloid bias, and the underlying molecular mechanisms remain poorly understood. Here, we performed single-cell multiome sequencing (scMultiome-seq) on human umbilical cord blood-derived CD34⁺ hematopoietic stem and progenitor cells to co-profile transcriptional and epigenetic adaptations within the same cells during ex vivo culture. Our analyses revealed reduced transcriptional and epigenetic HSC signatures, accompanied by markedly increased activity of myeloid-associated transcription factor motifs, providing molecular insight into the functional decline and myeloid bias of cultured HSCs. We further observed substantial functional heterogeneity among phenotypically defined HSCs following culture. To address these limitations, we established a niche-mimetic culture system that integrates intrinsic and extrinsic bone marrow regulatory cues, including pharmacologic inhibition of the m6A reader YTHDF2 using the small molecule Y13-27, a three-dimensional microenvironment, and N-cadherin-mediated adhesion. This condition (3D-NcadP-Y) robustly preserved long-term repopulating capacity. When combined with the self-renewal agonist UM729, the resulting platform (3D-NcadP-Y-UM) uniquely enabled the expansion of serially transplantable long-term HSCs with balanced multilineage potential. scMultiome-seq and cellular analyses demonstrated that this condition preserves transcriptional and epigenetic long-term HSC signatures, maintains multilineage-associated transcription factor motifs, and limits excessive cell-cycle activation. Together, these findings elucidate molecular mechanisms underlying culture-induced HSC dysfunction and establish a niche-mimetic strategy for expanding functional human long-term HSCs while preserving key features of stemness.

DOI: https://doi.org/10.1182/blood.2026034240