bims-mithem 2025-11-30 papers

Issue of 2025–11–30
five papers selected by
Tim van Tienhoven, Erasmus Medical Center

bioRxiv. 2025 Nov 11. pii: 2025.11.10.687744. [Epub ahead of print]

Paradoxic enhancement of mitochondrial capacity in aging-specific megakaryopoiesis from hematopoietic stem cells.

Saran Chattopadhyaya, Stephanie Smith-Berdan, Sarah Huerta, E Camilla Forsberg.

Aging leads to quantitative and qualitative changes in platelet (Plt) production, with increased risk for thrombosis and other adverse cardiovascular events. Recent reports showed that aging promotes the emergence of non-canonical (nc) megakaryocyte progenitors (MkPs) directly from hematopoietic stem cells (HSCs), leading to the production of hyperactive Plts. The higher engraftment potential of ncMkPs compared to both young and old canonical (c)MkPs, contrasts with the functional decline of old HSCs. Emerging reports suggest that mitochondrial function critically regulates lineage commitment and cellular functionality, but how mitochondrial activity affects aging megakaryopoiesis is unknown. Here, we demonstrate that aged MkPs sustain unique mitochondrial activity, characterized by higher mitochondrial membrane potential, higher ATP content, and lower ROS levels compared to their younger counterparts. This contrasts with the dysfunctional mitochondrial state observed in old HSCs, suggesting lineage-specific organelle adaptations upon aging. Notably, we observed that the elevated mitochondrial capacity in aged MkPs is driven selectively by the age-specific ncMkPs. Paradoxically, in vivo pharmacological enhancement of mitochondrial activity in old mice reduced in situ Plt production, but increased Plt reconstitution by transplanted HSCs. These discoveries link uniquely regulated mitochondrial capacity to the intrinsic properties of age-specific MkPs, raising the possibility of therapeutic targeting to prevent aging-induced megakaryopoiesis.
HIGHLIGHTS: Aging-specific MkPs have elevated mitochondrial capacity, the inverse of aged HSCsMitochondrial enhancement differentially alters platelet counts in young and old miceEnhancement of mitochondrial capacity increases platelet repopulation by both young and old HSCs.

DOI: https://doi.org/10.1101/2025.11.10.687744

Bioengineering (Basel). 2025 Oct 27. pii: 1166. [Epub ahead of print]12(11):

Hematopoietic Stem Cell Aging: Mechanisms, Microenvironment Influences, and Rejuvenation Strategies.

Jiaqi Cui, Xincan Li, Bin Liu, Cheng Dong, Yun Chang.

Hematopoietic stem cells (HSCs) are essential for lifelong blood production and immune homeostasis. However, aging induces functional declines in HSCs, leading to hematological disorders, immune dysfunction, and increased susceptibility to malignancies. This review explores the biological underpinnings of HSC aging, highlighting the intrinsic and extrinsic factors that drive this process. We discuss the molecular and cellular mechanisms contributing to HSC aging, including genetic instability, epigenetic alterations, metabolic shifts, and inflammation signaling. Additionally, we examine the role of the bone marrow microenvironment in modulating HSC aging, emphasizing the impact of niche interactions, stromal cell dysfunction, and extracellular matrix remodeling. To advance our understanding of HSC aging, pluripotent stem cell differentiation platforms provide a valuable tool for modeling aged HSC phenotypes and identifying potential therapeutic targets. We review current strategies for HSC rejuvenation, including metabolic reprogramming, epigenetic modifications, pharmacological interventions, and niche-targeted approaches, aiming to restore HSC function and improve regenerative potential. Finally, we present emerging perspectives on the clinical implications of HSC aging, discussing potential translational strategies for combating age-associated hematopoietic decline. By integrating insights from stem cell biology, aging research, and regenerative medicine, this review provides a comprehensive overview of HSC aging and its therapeutic potential. Addressing these challenges will be critical for developing interventions that promote hematopoietic health and improve outcomes in aging populations.

Keywords: hematopoietic stem cell aging; microenvironment niche; molecular and cellular mechanisms; pluripotent stem cell; rejuvenation strategies

DOI: https://doi.org/10.3390/bioengineering12111166

Int J Mol Sci. 2025 Nov 19. pii: 11191. [Epub ahead of print]26(22):

Beyond Thrombopoiesis: The Immune Functions of Megakaryocytes in Bacterial Infections and Sepsis.

Marina Leardini-Tristão, Meenakshi Banerjee.

Megakaryocytes (MKs) are specialized hematopoietic cells long recognized for their ability to produce platelets. Increasing evidence now highlights MKs as multifunctional immune effectors that bridge hematopoiesis with host immunity. In the bone marrow (BM), MKs arise through thrombopoietin (TPO)-mediated differentiation of hematopoietic stem cells (HSCs) and show substantial heterogeneity, with discrete subsets specialized for platelet production (thrombopoiesis), HSC niche maintenance, or immune modulation. Outside the BM, MKs in the lungs and spleen perform tissue-specific immune functions, including pathogen recognition, phagocytosis, antigen presentation, and secretion of cytokines. During bacterial infections and sepsis, infectious or inflammatory cues reprogram MKs to amplify immune signaling and host responses, but can also drive coagulopathy and contribute to organ failure. Collectively, these findings redefine MKs as dynamic immunomodulatory cells positioned at the interface of thrombopoiesis and innate and adaptive immunity. In this review, we synthesize emerging literature on MK biogenesis, functional diversity, and immune modulation, with a special focus on their roles in bacterial infections and sepsis.

Keywords: bacteria; bacteria-host interaction; immune cells; immune response; megakaryocytes; platelet production; sepsis

DOI: https://doi.org/10.3390/ijms262211191

bioRxiv. 2025 Oct 06. pii: 2025.10.05.680535. [Epub ahead of print]

Transcriptional and epigenetic repression of hematopoietic stem cells underlies bone marrow failure after spinal cord injury.

Kyleigh A Rodgers, Elizabeth A R Garfinkle, Kristina A Kigerl, Elham Asghari Adib, Katherine A Mifflin, Jodie Hall, Rohan Kulkarni, Cankun Wang, Chinmayee Goda, Ana C Rodrigues Dias, Zhen Guan, Malith Karunasiri, Qin Ma, Katherine E Miller, Adrienne M Dorrance, Phillip G Popovich.

Spinal cord injury (SCI) exerts profound systemic effects that extend beyond the nervous system, including the onset of bone marrow failure. Here, we show that SCI impairs the ability of hematopoietic stem cells (HSCs) to exit quiescence, proliferate, and differentiate, ultimately compromising long-term hematopoiesis. Using in-vivo transplantation assays, single-cell transcriptomics, and chromatin accessibility profiling, we show that SCI suppresses canonical stress-induced transcriptional programs in HSCs, including those governing cell cycle progression and DNA repair. These transcriptional changes are accompanied by epigenetic remodeling, with reduced chromatin accessibility at key genomic loci required for genome maintenance. Functionally, SCI HSCs exhibit impaired proliferation, persistent DNA damage, and an inability to resolve oxidative stress, even in the absence of ongoing injury. These defects culminate in bone marrow failure and pancytopenia in recipient mice. Our findings reveal a previously unrecognized systemic consequence of SCI and underscore the need for therapeutic strategies to preserve hematopoietic integrity following SCI.
Key Findings: SCI prevents stress-induced transcriptional programs in HSCs.DNA repair genes in HSPCs are epigenetically silenced after SCI.SCI HSCs accumulate ROS and DNA damage.SCI HSCs are hypersensitive to genotoxic stress.SCI HSCs fail long-term hematopoiesis post-transplant.

DOI: https://doi.org/10.1101/2025.10.05.680535

bioRxiv. 2025 Oct 27. pii: 2025.10.27.684807. [Epub ahead of print]

Mitofusin agonists enhances long-term engraftment and potency of HSC cultures in vivo.

Alyssa Biondo, Gabriela Candelaria, Daniel Jin, Emily Lin, Daniel McLaughlin, Zhaolun Liang, Katherine Leong, Christopher D Hillyer, Hans-Willem Snoeck, Larry L Luchsinger.

Umbilical cord blood (CBU) is a valuable source of hematopoietic stem cells (HSCs) due to its superior donor compatibility and lower incidence of graft-versus-host disease. However, its limited HSC content restricts its use in adult transplantation, necessitating new targets for ex vivo expansion and improved HSC potency. Mitofusin 2 (MFN2), a mitochondrial membrane fusion protein, is necessary for preserving HSC function and agonists of mitofusin activity have been characterized. We report that ex vivo culture of CBU HSCs with mitofusin agonists (MAs) enhances long-term repopulating activity by over five-fold in both primary and secondary transplantation assays without changes of total nucleated cells or phenotypic HSCs. Mechanistically, MA-treated HSCs show suppressed protein synthesis, increased autophagic flux, and elevated lysosomal acidification. Transcriptomic analysis implicates downregulation of MTOR signaling, and immunoprecipitation studies confirm a direct interaction between MFN2 and MTOR. These data support a model in which fusion-competent MFN2 sequesters MTOR, promoting a catabolic state that preserves HSC potency. Our findings suggest a novel MFN2-MTOR regulatory axis that enhances the functional expansion of human HSCs for potential therapeutic application.

DOI: https://doi.org/10.1101/2025.10.27.684807