bims-mithem 2026-06-14 papers

Issue of 2026–06–14
three papers selected by
Tim van Tienhoven, Erasmus Medical Center

Mech Ageing Dev. 2026 Jun 11. pii: S0047-6374(26)00064-3. [Epub ahead of print] 112212

Aging-Driven Reprogramming of CD34⁺ Hematopoietic Stem Cells in Leukemogenesis: Mechanisms and Therapeutic Implications.

Surya Nath Pandey, Muhammad Afzal, A Rekha, Mano Priya Vijayan, Prerna Uniyal, Chandana Maji, Abida Khan, Lakshmi Thangavelu, Karuppiah Nagaraj.

Aging is a major driver of hematological impairment and a significant risk factor for hematologic malignancies. CD34⁺ hematopoietic stem and progenitor cells (HSPCs) represent a critical cellular compartment in which age-related changes converge to promote leukemogenesis. This review synthesizes contemporary findings on the interplay between intrinsic hallmarks of aging, including genomic instability, telomere attrition, epigenetic drift, and mitochondrial dysfunction, and extrinsic factors, including chronic inflammation and bone marrow niche remodeling, in the reprogramming of CD34⁺ cell fate. These alterations promote clonal hematopoiesis of indeterminate potential (CHIP), impair immune competence, and increase susceptibility to malignant transformation. Special attention is directed towards CD34⁺CD38⁻ subsets, which possess leukemic stem cell (LSC) functionality and demonstrate resistance to standard treatments. Emerging biomarkers, including CD123, CD96, IL1RAP, and CD133, are discussed in relation to disease progression and therapeutic targeting. We emphasize how aging-related inflammatory signaling and metabolic changes preferentially benefit pre-leukemic clones. Ultimately, we investigate therapeutic approaches designed to disrupt leukemogenesis by focusing on aging mechanisms, the senescent microenvironment, and vulnerabilities specific to leukemic stem cells (LSCs). This review contextualizes CD34⁺ cell biology within aging mechanisms, offering a cohesive view on illness onset and highlighting prospects for early intervention in older populations.

Keywords: Aging; CD34(+) cells; Clonal hematopoiesis; Hematopoietic stem cells; Leukemic stem cells; Leukemogenesis

DOI: https://doi.org/10.1016/j.mad.2026.112212

Stem Cell Reports. 2026 Jun 11. pii: S2213-6711(26)00170-0. [Epub ahead of print] 102959

Multiome-based identification of molecular markers for prospective identification of platelet-biased HSCs.

Bowen Zhang, Yiran Meng, Esther Rodríguez Correa, Xiying Ren, Alexandre Fagnan, Michael D Milsom, Claus Nerlov.

Platelet-biased hematopoietic stem cells (PLT-HSCs) play key roles in normal physiology, aging, and blood cancer. However, currently, no markers allow their accurate identification or prospective isolation. We here combine single-mouse hematopoietic stem cell (HSC) gene expression, chromatin accessibility, and surface proteome profiling to identify subtype-specific markers. Using machine learning, we identified markers (CD61hiCD274hiCD357loCD27lo) that isolate PLT-HSCs to high purity, validated by single-cell transplantation. Furthermore, we develop a minimal expression marker panel that discriminates PLT- and multi-lineage (MUL-)HSCs using microfluidics-based single-cell RT-qPCR. We show that both methods detect the age-associated increase in PLT-HSCs, while poly(I-C)-induced chronic inflammation did not alter HSC lineage bias. In contrast, romiplostim treatment increased MUL-HSC prevalence. Finally, using spectral flow cytometry to simultaneously quantify cell cycle and HSC lineage bias, we show that platelet depletion selectively activates PLT-HSCs. Together, these approaches allow accurate isolation of PLT-HSCs and robust quantification of lineage bias under perturbation.

Keywords: hematopoietic stem cells; lineage bias; platelet-biased HSCs; single-cell multiomics

DOI: https://doi.org/10.1016/j.stemcr.2026.102959

Int J Mol Sci. 2026 May 30. pii: 4966. [Epub ahead of print]27(11):

Sex Differences in Mitochondrial Function: Endocrine Regulation, Immunometabolic Signaling, and Implications for Health and Disease.

Hanna Bynum, Kristin S Edwards.

Mitochondria are central regulators of cellular bioenergetics, redox balance, and signaling pathways that integrate metabolic and immune responses. Emerging evidence indicates that biological sex is an important determinant of mitochondrial function, in part through the regulatory effects of sex hormones on mitochondrial biogenesis, oxidative phosphorylation, reactive oxygen species production, and quality control mechanisms. Estrogen, testosterone, and progesterone differentially modulate mitochondrial dynamics, substrate utilization, antioxidant capacity, and immune signaling, resulting in distinct mitochondrial phenotypes that may influence disease susceptibility across the lifespan. In this review, we synthesize current knowledge on the mechanistic basis of sex differences in mitochondrial function and highlight mitochondria as key mediators linking endocrine signaling to immunometabolic regulation. We discuss how mitochondrial-derived signals, including mitochondrial reactive oxygen species, mitochondrial DNA release, and cardiolipin exposure, activate inflammatory pathways such as NF-κB, cGAS-STING, and NLRP3 inflammasome signaling. These pathways may contribute to chronic inflammation, gut barrier dysfunction, and systemic metabolic disruption. We further examine the impact of major endocrine transitions, including pregnancy, the postpartum period, menopause, and androgen imbalance in conditions such as polycystic ovary syndrome, on mitochondrial function and disease risk. Particular emphasis is placed on the gastrointestinal tract as a metabolically active and mitochondria-dependent interface, where mitochondrial dysfunction may contribute to epithelial barrier disruption, microbial dysbiosis, and systemic inflammation. Finally, we discuss emerging therapeutic strategies targeting mitochondrial function, including exercise, hormone-based therapies, mitochondria-targeted antioxidants, and interventions aimed at improving mitochondrial quality control. Understanding sex-specific mitochondrial regulation may provide a framework for improved endocrine stratification, mitochondrial phenotyping, and precision medicine approaches across diverse clinical contexts.

Keywords: endocrine disorders; estrogen; immunometabolism; mitochondria; mitochondrial dynamics; mitochondrial reactive oxygen species; oxidative phosphorylation; sex differences; sex hormones; testosterone

DOI: https://doi.org/10.3390/ijms27114966