bims-mithem 2026-07-26 papers

Issue of 2026–07–26
three papers selected by
Tim van Tienhoven, Erasmus Medical Center

Exp Hematol. 2026 Jul 22. pii: S0301-472X(26)00118-9. [Epub ahead of print] 105485

Reassessment of Hematopoietic Stem Cell Aging through Metabolic Uncoupling and Mitochondrial Resilience.

Hematopoietic stem cell (HSC) aging is often described as a gradual loss of stem cell fitness that culminates in impaired blood production, immune dysfunction, and increased susceptibility to hematologic disease. However, recent work suggests that this view is too simple. Rather than a uniform decline, aging appears to remodel the HSC compartment into metabolically and functionally distinct states, including maladaptive trajectories as well as surprisingly resilient subsets. In this review, we argue that HSC aging is best understood through the interplay of mitochondrial regulation, metabolic uncoupling, and niche-derived stress, with particular emphasis on how recent findings revise several longstanding assumptions in the field (Box 1).

Keywords: HSC aging; Hematopoietic resilience; Metabolic uncoupling; Mitochondrial metabolism; Niche

DOI: https://doi.org/10.1016/j.exphem.2026.105485

Sci Transl Med. 2026 Jul 22. 18(859): eadv0628

Premature senescence impairs hematopoietic stem cell function during sickle cell disease in mice and humans.

Sickle cell disease (SCD) is a blood disorder affecting millions worldwide. Emerging evidence reveals that SCD pathophysiology increases the risk of myeloid malignancies and hematopoietic stem cell (HSC) dysfunction, likely because of chronic stress on bone marrow. To investigate this further, we interrogated bone marrow hematopoietic stem and progenitor cells (HSPCs) from mice and individuals with SCD and observed molecular signatures of chronic cellular stress including oxidative stress, DNA damage, and hallmarks of senescence. Consistent with these findings, SCD HSPCs displayed transcriptomic dysregulation of senescence-associated molecular programs and diminished mitogen response with prolonged cell cycle kinetics during time-lapse live cell imaging. SCD mice displayed a marked loss of immunophenotypic bone marrow HSPCs by flow cytometry and functional blood repopulating HSPCs in transplantation studies, whereas human SCD bone marrow HSPCs exhibited poor ex vivo hematopoietic colony-forming ability, and these phenotypes were reversed after senescence-targeting therapy with either ABT-263 (navitoclax) or the combination of dasatinib and quercetin. Thus, treatment with senescence-targeting therapy improves bone marrow HSPC function in vivo in mice and ex vivo in cells from individuals with SCD and could represent a possible strategy to improve HSPC health, promote manufacture of high-quality bespoke clinical products, and potentially enhance the safety of potentially curative gene therapies using autologous HSPCs from individuals with SCD.

DOI: https://doi.org/10.1126/scitranslmed.adv0628

Trends Mol Med. 2026 Jul 23. pii: S1471-4914(26)00172-3. [Epub ahead of print]

Mitochondrial transfer: quality dictates immune-metabolic fate.

Kai Liu, Quazi T H Shubhra, Hui Zhang.

Horizontal mitochondrial transfer (HMT) outcomes are shaped by donor fitness and transfer context. We propose a post-transfer quality checkpoint that integrates membrane potential, oxidative damage, mitophagy, fusion, and fission to determine the recipient-cell's response. Depending on donor quality and recipient thresholds, HMT may drive bioenergetic restoration, inflammation, or tumor immune escape. This framework extends route-centered accounts of HMT toward a testable, quality-governed model for therapeutic intervention.

Keywords: immune-metabolic fate; mitochondrial quality; mitochondrial transfer; quality checkpoint

DOI: https://doi.org/10.1016/j.molmed.2026.07.002