bims-mithem Biomed News
on Mitochondria in Hematopoiesis
Issue of 2025–11–16
seven papers selected by
Tim van Tienhoven, Erasmus Medical Center
  1. Novel and emerging therapeutic strategies for clonal haematopoiesis.
  2. Accumulation of Lymphoid Progenitors with Defective B Cell Differentiation and of Putative Natural Killer Progenitors in Aging Human Bone Marrow.
  3. Normal Hematopoietic Stem Cells in Leukemic Bone Marrow Environment Undergo Morphological Changes Identifiable by Artificial Intelligence.
  4. Emerging Roles of Megakaryocytes in Immune Regulation and Potential Therapeutic Prospects.
  5. Mitochondrial Metabolic Reprogramming of Cortical Neurons by Prenatal Exposure to Corticosterone: A Shift from ATP Synthesis to Membrane Potential Maintenance.
  6. Triphenylphosphonium-based mitochondrial targeting in cancer therapy: mechanisms, progress, and perspectives.
  7. Targeting Mitochondrial Dynamics via EV Delivery in Regenerative Cardiology: Mechanistic and Therapeutic Perspectives.
  1. Haematologica. 2025 Nov 13.
    Novel and emerging therapeutic strategies for clonal haematopoiesis.
    Mohsen Hosseini, Steven M Chan.
      Clonal hematopoiesis (CH) arises when hematopoietic stem cells (HSCs) acquire mutations that confer a competitive advantage over wild-type HSCs, leading to their expansion in the bone marrow with clonal progeny that circulate in the blood and are most readily detected through peripheral blood sequencing. The prevalence of CH increases with age and is linked to a higher risk of hematologic malignancies and various non-malignant diseases, particularly atherosclerotic cardiovascular disease. CH is not merely a biomarker; it actively contributes to the pathogenesis of these agerelated conditions. Therefore, targeting the expansion of mutant clones and their downstream effects offers an opportunity to prevent these adverse health outcomes. CH involves mutation-specific biological changes that sustain the abnormal HSC phenotype, including epigenetic dysregulation, aberrant inflammatory signaling, metabolic reprogramming, and altered intracellular signaling pathways. A deeper understanding of these processes has led to the development of targeted therapeutic approaches. This review addresses the practical challenges of implementing interventions against CH, focusing on balancing risk and benefit and selecting appropriate patients. It discusses emerging treatments targeting the pathogenic mechanisms in CH, such as epigenetic modulators, anti-inflammatory therapies, metabolic inhibitors, and signaling pathway inhibitors. We also highlight potential novel therapeutic strategies on the horizon, such as immune-based approaches for selective clonal elimination and gene-editing therapies to correct causative mutations. These advances reframe CH as a potentially modifiable condition rather than an inevitable consequence of aging, creating opportunities for early intervention before progression to overt disease.
    DOI:  https://doi.org/10.3324/haematol.2025.287443
  2. Int J Mol Sci. 2025 Oct 28. pii: 10467. [Epub ahead of print]26(21):
    Accumulation of Lymphoid Progenitors with Defective B Cell Differentiation and of Putative Natural Killer Progenitors in Aging Human Bone Marrow.
    Laura Poisa-Beiro, Jonathan J M Landry, Aleksandr Cherdintsev, Michael Kardorff, Volker Eckstein, Laura Villacorta, Judith Zaugg, Anne-Claude Gavin, Vladimir Benes, Simon Raffel, Anthony D Ho.
      In animal models, elimination of the senescent cells in the hematopoietic stem cells (HSCs) compartment leads to the rejuvenation of hematopoiesis. Whether this treatment principle can be applied to the human system remains controversial. The identification of senescent cells in human bone marrow poses another major challenge. To address these questions, we have studied hematopoietic stem and progenitor cells (HSPCs, CD34+) from the bone marrow of 15 healthy human subjects (age range: 19-74 years). Single-cell RNA sequencing, functional transcriptome analysis, and development trajectory studies were performed. In a previous report, we demonstrated the accumulation of a senescent population in the aging HSC compartment. The present study focuses on the differences with age downstream in the lymphoid trajectory. While a reduction in B progenitors in the early lymphoid compartment can be confirmed, the accumulation of a lymphoid cluster downstream upon aging is novel and remarkable. This cluster comprises cells with a significant deficiency in B differentiation markers, as well as 9.4% cells with transcriptome signatures of memory-like natural killer (NK) progenitors. Applying our analysis algorithm to other human bone marrow datasets from the literature, we are able to validate the presence of this unique cluster in aged lymphoid progenitors. The accumulation of a population comprising cells defective in B differentiation potential, as well as cells with transcriptome features of memory-like NK progenitors represents a novel hallmark for senescence in the late development trajectory of human lymphoid compartment.
    Keywords:  aging; hematopoietic stem and progenitor cells; human bone marrow; immunosenescence; lymphoid compartment; memory-like NK cells; natural killer progenitors; senescence; senolysis
    DOI:  https://doi.org/10.3390/ijms262110467
  3. Int J Mol Sci. 2025 Oct 24. pii: 10354. [Epub ahead of print]26(21):
    Normal Hematopoietic Stem Cells in Leukemic Bone Marrow Environment Undergo Morphological Changes Identifiable by Artificial Intelligence.
    Dongguang Li, Athena Li, Ngoc DeSouza, Shaoguang Li.
      Leukemia stem cells (LSCs) in numerous hematologic malignancies are generally believed to be responsible for disease initiation, progression/relapse and resistance to chemotherapy. It has been shown that non-leukemic hematopoietic cells are affected molecularly and biologically by leukemia cells in the same bone marrow environment where both non-leukemic hematopoietic stem cells (HSCs) and LSCs reside. We believe the molecular and biological changes of these non-leukemic HSCs should be accompanied by the morphological changes of these cells. On the other hand, the quantity of these non-leukemic HSCs with morphological changes should reflect disease severity, prognosis and therapy responses. Thus, identification of non-leukemic HSCs in the leukemia bone marrow environment and monitoring of their quantity before, during and after treatments will potentially provide valuable information for correctly handling treatment plans and predicting outcomes. However, we have known that these morphological changes at the stem cell level cannot be extracted and identified by microscopic visualization with human eyes. In this study, we chose polycythemia vera (PV) as a disease model (a type of human myeloproliferative neoplasms derived from a hematopoietic stem cell harboring the JAK2V617F oncogene) to determine whether we can use artificial intelligence (AI) deep learning to identify and quantify non-leukemic HSCs obtained from bone marrow of JAK2V617F knock-in PV mice by analyzing single-cell images. We find that non-JAK2V617F-expressing HSCs are distinguishable from LSCs in the same bone marrow environment by AI with high accuracy (>96%). More importantly, we find that non-JAK2V617F-expressing HSCs from the leukemia bone marrow environment of PV mice are morphologically distinct from normal HSCs from a normal bone marrow environment of normal mice by AI with an accuracy of greater than 98%. These results help us prove the concept that non-leukemic HSCs undergo AI-recognizable morphological changes in the leukemia bone marrow environment and possess unique morphological features distinguishable from normal HSCs, providing a possibility to assess therapy responses and disease prognosis through identifying and quantitating these non-leukemic HSCs in patients.
    Keywords:  artificial intelligence; hematopoietic stem cells; leukemia stem cells; polycythemia vera
    DOI:  https://doi.org/10.3390/ijms262110354
  4. Cells. 2025 Oct 27. pii: 1677. [Epub ahead of print]14(21):
    Emerging Roles of Megakaryocytes in Immune Regulation and Potential Therapeutic Prospects.
    Seungjun Kim, Kiwon Lee.
      Megakaryocytes (MKs) have traditionally been viewed as terminal hematopoietic cells responsible solely for platelet production. However, recent advances in imaging and single-cell transcriptomics have revealed substantial heterogeneity among MK populations and diverse functions beyond thrombopoiesis. MKs actively participate in innate and adaptive immunity, modulate the hematopoietic stem cell (HSC) niche, and adapt to physiological and pathological stimuli. Located in distinct anatomical sites such as bone marrow and lung, MKs exhibit compartment-specific specializations that enable them to serve as critical integrators of hemostatic, immune, and regenerative processes. Experimental models using human pluripotent stem cells and inducible MKs have enhanced mechanistic insights, while innovative bioreactor platforms and xenotransplantation strategies advance translational applications in platelet production and therapy. Furthermore, immune MK subsets derived from pluripotent stem cells show promising therapeutic potential for modulating inflammation and autoimmune diseases. Continued exploration of MK diversity, tissue-specific roles, and intercellular communication will unlock new opportunities for leveraging MK plasticity in regenerative medicine, immunotherapy, and hematologic disorders, repositioning these versatile cells as central players in systemic homeostasis and defense.
    Keywords:  immune MK; megakaryocyte diversity; pluripotent stem cells
    DOI:  https://doi.org/10.3390/cells14211677
  5. Exp Neurobiol. 2025 Nov 11.
    Mitochondrial Metabolic Reprogramming of Cortical Neurons by Prenatal Exposure to Corticosterone: A Shift from ATP Synthesis to Membrane Potential Maintenance.
    Khulan Amarsanaa, Michidmaa Badarch, Hee-Young Kim, Oh-Bin Kwon, Eun-Bok Baek, Eun-A Ko, Sung-Cherl Jung.
      Mitochondrial bioenergetics plays a fundamental role in neuronal development and function. Prenatal exposure to corticosterone in rats (Corti. Pup) has previously been shown to cause delayed neurodevelopment and synaptic plasticity deficits, showing attention deficit hyperactivity disorder (ADHD) - like behaviors. However, the underlying mitochondrial metabolic adaptations remain unclear. This study investigated mitochondrial function and metabolic remodeling in prefrontal cortex neurons of Corti.Pups, focusing on oxidative phosphorylation, calcium handling, and redox balance. We assessed neuronal viability, reactive oxygen species (ROS) production, and oxygen consumption rate (OCR) through experiments conducted in both neuron-glia co-culture and neuron-only conditions. Furthermore, we evaluated electron transport chain (ETC) activity, mitochondrial membrane potential (MMP), and mitochondrial Ca2+ uptake in purified isolated mitochondria. In results, Corti.Pup neurons exhibited increased vulnerability to glutamate-induced excitotoxicity in the absence of glial support. Despite reduced ROS production, these neurons showed elevated mitochondrial OCR and proton leak, coupled with decreased non-mitochondrial OCR and ETC complex activity. Surprisingly, MMP remained elevated despite ETC dysfunction, and mitochondrial Ca2+ uptake was suppressed. These features indicate mitochondrial metabolic reprogramming, prioritizing MMP maintenance over ATP synthesis. The observed mitochondrial inefficiency and compensatory adaptations may impair energy production, contributing to delayed neuronal development in Corti.Pups. These findings suggest that mitochondrial dysfunction and metabolic remodeling play central roles in the pathogenesis of neurodevelopmental disorders such as ADHD.
    Keywords:  ADHD; Corticosterone; Mitochondria; Neurodevelopment; OCR
    DOI:  https://doi.org/10.5607/en25025
  6. Chem Commun (Camb). 2025 Nov 14.
    Triphenylphosphonium-based mitochondrial targeting in cancer therapy: mechanisms, progress, and perspectives.
    Min Yang, Jiaming Ou, Haibo Yan, Yun He, Linling Gan, Shao-Lin Zhang.
      Targeting mitochondria has emerged as a promising anticancer strategy, as these organelles regulate tumor metabolism, apoptosis, and drug resistance. Triphenylphosphonium (TPP)-based strategies leverage the mitochondrial membrane potential to achieve selective accumulation in cancer cells, thereby providing a versatile platform for advancing precision cancer therapy. This review summarizes recent progress in the development of TPP-based anticancer agents, their mechanisms of action, and the current challenges. We also highlight future research directions, which will focus on designing multifunctional TPP molecules, integrating TPP-based therapeutics with complementary treatment modalities, and developing tissue- or cell-specific smart delivery systems. Additional promising strategies include combining TPP-based therapies with immunotherapy to overcome tumor immune evasion, targeting mitochondrial DNA to disrupt cancer bioenergetics, and employing TPP conjugates for fluorescence imaging to monitor drug distribution and mitochondrial targeting efficiency. Collectively, these approaches are expected to accelerate the clinical translation of TPP-mediated mitochondrial therapies, opening new avenues for precision oncology.
    DOI:  https://doi.org/10.1039/d5cc05709d
  7. Cells. 2025 Nov 05. pii: 1738. [Epub ahead of print]14(21):
    Targeting Mitochondrial Dynamics via EV Delivery in Regenerative Cardiology: Mechanistic and Therapeutic Perspectives.
    Dhienda C Shahannaz, Tadahisa Sugiura, Brandon E Ferrell, Taizo Yoshida.
      Mitochondrial dysfunction is a key contributor to cardiac injury and heart failure, and extracellular vesicles (EVs) have emerged as promising therapeutic agents due to their ability to deliver mitochondrial-targeted cargo. This review systematically maps the evidence on how EVs modulate mitochondrial dynamics-including fusion, fission, mitophagy, and biogenesis-in regenerative cardiology. We comprehensively searched PubMed, Scopus, and Web of Science up to September 2025 for original studies. A total of 48 studies were included, with most utilizing EVs from mesenchymal stem cells, induced pluripotent stem cells, or cardiac progenitors. The review found that EV cargo influences key pathways such as DRP1 and MFN2, restores mitochondrial membrane potential, reduces ROS accumulation, and improves cardiomyocyte survival. While engineered EVs showed enhanced specificity, a lack of standardized preparation and quantitative assessment methods remains a significant challenge. We conclude that EV-mediated mitochondrial modulation is a promising strategy for cardiac repair, but the field needs harmonized protocols, deeper mechanistic understanding, and improved translational readiness to advance beyond preclinical research. The future of this research lies in integrating systems biology and precision targeting.
    Keywords:  EV-based drug delivery; cardiac regeneration; extracellular vesicles (EVs); heart failure therapy; mitochondrial biogenesis and mitophagy; mitochondrial dynamics; mitochondrial transfer; regenerative cardiology; stem cell-derived EVs; translational cardiovascular medicine
    DOI:  https://doi.org/10.3390/cells14211738
This page is being maintained by Thomas Krichel. It was last updated on 2025‒11‒17 at 13:41.