bims-mithem 2025-12-21 papers

Issue of 2025–12–21
four papers selected by
Tim van Tienhoven, Erasmus Medical Center

Eur J Histochem. 2025 Sep 22. 69(4):

The hematopoietic stem cells supportive megakaryocytes as shapers of the bone marrow niche.

Francesca Arciprete, Viola Velardi, Paola Verachi, Claudio Carta, Antonio Di Virgilio, Vincenzo Roberti, Giorgio Vivacqua, Rosalba Rana, Maria Zingariello.

The bone marrow (BM) niche plays a pivotal role in regulating the fate of hematopoietic stem cells (HSCs), and its integrity changes significantly during aging and in rare hematological disease, as in myelofibrosis (MF). In this study, we investigated how the localization and dynamics of HSCs are influenced under physiological and pathological conditions by a newly identified by HSC-supportive megakaryocytes (MKs) subpopulation. Using huCD34tTA/TetO-H2BGFP reporter mice, we analyzed HSCs distribution within the BM and quantified nuclear green fluorescent protein (GFP) intensity to assess the repopulating potential of aged controls and mutated Gata1low mice for MF. In the control group of aged mice, cells with high levels of GFP are clustered, and adjacent to cells morphologically identifiable as supportive MKs. These clusters displayed homogeneous GFP intensity, indicating that HSCs with similar functional properties tend to co-localize in proximity to supportive MKs. By contrast, in aged huCD34/TET/Gata1low mice, GFP cells were predominantly isolated and showed reduced fluorescence intensity. Although the frequency of MKs with a supportive phenotype was increased in MF mice, analyses of GFP revealed that the ability of these MKs to maintain the HSCs in their niche was significantly impaired. Our results provide new insights on the maladaptive remodeling of the BM niche. They highlight the supportive role of MKs as potential key regulators of HSCs homeostasis. Despite their numerical expansion in MF, these cells are functionally compromised, thereby contributing to altered HSCs localization, mobilization, and to hematopoietic failure.

Keywords: Bone marrow; aging; hematopoiesis; hematopoietic stem cells; megakaryocyte; myelofibrosis

DOI: https://doi.org/10.4081/ejh.2025.4424

NPJ Aging. 2025 Dec 16. 11(1): 99

Mitochondrial dysfunction in cellular senescence: a bridge to neurodegenerative disease.

Adam J Hruby, Ryo Higuchi-Sanabria.

Senescent cells, characterized by a state of irreversible proliferative arrest and inflammatory profile, have emerged as drivers of age-related decline. Growing evidence suggests that alterations in mitochondrial function and morphology play a key role in the induction and maintenance of senescence, as well as in promotion of the proinflammatory senescence-associated secretory phenotype (SASP). In this review, we seek to survey the relationship between mitochondrial dysfunction and senescence, focusing on the consequences of changes in oxidative phosphorylation efficiency, calcium handling, mitochondrial metabolites, mitochondrial dynamics and quality control, and release of damage-associated molecular patterns. We first describe these changes before illustrating the pathways and mechanisms through which mitochondrial dysfunction results in cell cycle arrest and the SASP. Lastly, we showcase evidence relating cellular senescence to neurodegenerative disease and propose that mitochondrial dysfunction may act as a bridge between the two.

DOI: https://doi.org/10.1038/s41514-025-00291-4

Cell Mol Life Sci. 2025 Dec 19. 82(1): 443

IL-1 signaling and inflammasomes in acute myeloid leukemia: mechanisms and therapeutic opportunities.

Alessandra Mortellaro, Sara Mastaglio, Marta Muzio.

Acute myeloid leukemia (AML) is a heterogenous disease characterized by the accumulation of immature myeloid blasts with distinct genetic mutations in the bone marrow and peripheral blood. AML co-evolve with other components of specialized bone marrow niches within a microenvironment enriched in cytokines and inflammatory cells; among these, interleukin-1 (IL-1) may act as a tumor driver. This review examines two complementary aspects of AML biology in relation to IL-1. First, we describe the functional activity of IL-1 and the signaling pathways triggered by the IL-1 receptor in malignant cells, along with preclinical and clinical studies targeting this pathway in AML. Second, we discuss the mechanisms regulating the release of mature IL-1β through the activation of different inflammasomes. Inflammasomes, particularly NLRP3, are emerging as key contributors to AML pathophysiology. Beyond IL-1 release, NLRP3 may interface with cellular stress responses and pyroptosis, thereby influencing both AML cells and their microenvironment through multiple mechanisms. Inflammasome signaling may act as a driver of therapy resistance while also representing a promising therapeutic target.

Keywords: AML; Acute myeloid leukemia; IL-1; Inflammasome; Interleukin-1; NLRP3

DOI: https://doi.org/10.1007/s00018-025-05966-5

Leukemia. 2025 Dec 19.

Dynamics of clonal hematopoiesis and cellular responses to stress-induced toxicity in autologous stem cell transplantation.

Catarina M Stein, Raphael Hablesreiter, Friederike Christen, Pelle Löwe, Coral Fustero-Torre, Klara Kopp, Benjamin N Locher, Lena Nitsch, Robert Altwasser, Johanna Franziska Kerschbaum, Lars Bullinger, Leif S Ludwig, Paulina M Strzelecka, Frederik Damm.

Autologous stem cell transplantation (ASCT) involves harvesting hematopoietic stem and progenitor cells (HSPCs) prior to chemotherapy and subsequent repopulation of the bone marrow. This process imposes a bottleneck, providing a framework to dissect the unresolved short- and long-term clonal dynamics during hematopoietic reconstitution. By integrating bulk error-corrected targeted sequencing of clonal hematopoiesis (CH)-associated genes with mitochondrial single-cell Assay for Transposase-Accessible Chromatin sequencing (mtscATAC-seq), we characterized mutational trajectories in frequently altered hematological genes and traced clonal evolution through somatic mitochondrial DNA variants, revealing post-transplant cellular heterogeneity and clonal architecture. Among 60 patients (multiple myeloma, n = 51; non-Hodgkin lymphoma, n = 6; Hodgkin lymphoma, n = 3), CH-associated mutations were identified in 53% pre-ASCT, predominantly involving DNMT3A. A transient increase in mutation counts and gene diversity occurred 10-25 days post-ASCT, with a gradual clonal expansion two years post-transplantation. Tandem ASCT amplified clonal complexity, with a twofold increase in mutation count and gene-level diversity, while preserving clonal trajectories across both transplant courses. Mitochondrial single-cell profiling in longitudinal samples of 3 patients showed patient-specific immune reconstitution and clonal dynamics, with balanced multilineage output from graft HSPCs. Collectively, our findings provide a firsthand comprehensive view of ASCT-induced clonal dynamics and immune reconstitution, paving the way for targeted gene-specific post-transplant monitoring.

DOI: https://doi.org/10.1038/s41375-025-02823-z