bims-mithem Biomed News
on Mitochondria in Hematopoiesis
Issue of 2026–10–11
two papers selected by
Tim van Tienhoven, Erasmus Medical Center
  1. Suppressing glutamate dehydrogenase guides hematopoietic stem cell divisions into self-renewal.
  2. Getting comfortable: clonal haematopoiesis creates a senescent niche for expansion.
  1. Nat Commun. 2026 09 05. pii: 10558. [Epub ahead of print]17(1):
    Suppressing glutamate dehydrogenase guides hematopoietic stem cell divisions into self-renewal.
    Michihiro Hashimoto, Michie Uchikawa, Yuichiro Arima, Akiyasu Iwase, Ayano Yahagi, Mizuki Ishimaru, Tomomasa Yokomizo, Ayako Nakamura-Ishizu, Yosuke Tanaka, Kenichi Miharada, Hiroki Kurihara, Goro Sashida, Toshio Suda, Terumasa Umemoto.
      Hematopoietic stem cells (HSCs) self-renew to expand their pool but often differentiate upon division. Thus, it remains unclear how HSCs maintain their stemness during or after division. Here, we show that the suppression of glutamate dehydrogenase (Glud1), a key enzyme responsible for glutamate (Glu) catabolism, supports the maintenance of HSCs during division. We find that self-renewing mouse HSCs during hematopoietic regeneration exhibited lower intracellular Glu levels compared to HSCs differentiating during ex vivo culture. We therefore focus on the negative regulation of Glu catabolic reactions as a candidate factor to maintain HSCs during division, and find that treatment with the Glud1 inhibitor, R162, maintains a subset of HSCs that would otherwise differentiate during division under normal culture conditions. This treatment successfully results in an approximately 500-fold expansion of functional mouse HSCs that maintain expression pattern of conventional stem cell markers over a 30-day culture period. Importantly, this positive effect of Glud1 inhibition is independent of suppressing cell divisions and dependent on robust JAK2-STAT signaling. Overall, our findings propose that Glud1 inhibition, coupled with robust JAK2-STAT signaling, characterizes a functional HSC state during division, enabling ex vivo expansion of mouse HSCs under conventional culture conditions.
    DOI:  https://doi.org/10.1038/s41467-026-77151-6
  2. Cancer Res. 2026 Oct 05.
    Getting comfortable: clonal haematopoiesis creates a senescent niche for expansion.
    Nieves Garcia-Gisbert, Giovanna Mantica, Elisa Laurenti.
      Clonal haematopoiesis (CH) is characterized by the age-associated expansion of mutant haematopoietic clones. How these clones expand, interact with the niche, and maintain a competitive advantage remains poorly understood. In a recent study published in Nature Cell Biology, Mistry and colleagues uncover that senescence in the bone marrow stromal microenvironment is a key contributor to the clonal growth of haematopoietic stem and progenitor cells (HSPCs) carrying CH mutations. Using mouse models and primary human samples, they show that mutant haematopoietic cells induce MSC senescence through contact-independent, cytokine-mediated signalling involving TNF-α, IL-6 and STAT3. Senescent MSCs preferentially support mutant haematopoietic stem and progenitor cells (HSPCs) over wild-type cells. Moreover, genetic or pharmacological depletion of senescent non-haematopoietic cells reduces CH burden and delays progression towards myeloid neoplasia in mice. By demonstrating that the premalignant niche is actively remodelled to favor mutant haematopoiesis, this study identifies MSC senescence as a relevant mechanism regulating CH evolution and a potential target for early disease intervention.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-4171
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