bims-mithem 2025-09-21 papers

Issue of 2025–09–21
three papers selected by
Tim van Tienhoven, Erasmus Medical Center

Cell Rep. 2025 Sep 17. pii: S2211-1247(25)01067-8. [Epub ahead of print]44(10): 116296

Mitochondrial-activity-driven hematopoietic stem cell fate and lineage choice is first established in the aorta-gonad-mesonephros.

Aishwarya Prakash, Maneesha S Inamdar.

Mitochondrial metabolism determines bone marrow hematopoietic stem cell (HSC) heterogeneity and influences their repopulation potential, though its embryonic origins remain unclear. We show that during the endothelial-to-hematopoietic transition in the mouse embryo, dynamic changes in mitochondrial activity drive the production of hematopoietic stem and progenitor cells (HSPCs) with differing potencies. Lowering mitochondrial activity in the aorta-gonad-mesonephros (AGM) by pharmacological or genetic means activates Wnt signaling to promote HSPC expansion. Further, mitochondrial membrane potential (MMP) gives rise to functional heterogeneity in HSPCs. In-vitro and in-vivo functional assays and single-cell transcriptomics showed that MMPlow HSPCs in the AGM are myeloid biased, with enhanced differentiation potential, whereas MMPhigh HSPCs are lymphoid biased, with diminished differentiation potential. Mechanistically, low mitochondrial activity in HSPCs upregulates phosphoinositide 3-kinase signaling to promote differentiation. These insights into the initiation of metabolic heterogeneity could be leveraged to isolate the distinct HSPC subsets and to efficiently generate the desired lineages.

Keywords: CP: Developmental biology; PI3K signaling; Wnt signaling; cell fate; endothelial to hematopoietic transition; hematopoiesis; hematopoietic stem and progenitor cell; lymphoid; metabolism; mitochondria; myeloid

DOI: https://doi.org/10.1016/j.celrep.2025.116296

Trends Cancer. 2025 Sep 16. pii: S2405-8033(25)00204-3. [Epub ahead of print]

Optimizing mitochondria function in immune cells: implications for cancer immunotherapy.

Huiyu Li, Wenyi Jin, Junhong Liu, Yundong Zhou, Xiaoli Shan, Yubiao Zhang, Yongliang Kou, Chunyan Deng, Cheng Jin, Junjie Kuang, Yui-Leung Lau, João Conde, Baozhen Huang, Queran Lin.

The tumor microenvironment (TME) imposes profound metabolic and functional constraints on immune cells, with mitochondrial dysfunction emerging as a pivotal driver of immunosuppression. While mitochondrial metabolism is well recognized for its role in energy production and cellular homeostasis, its dynamic regulation of immune cell activation, differentiation, and exhaustion within the TME remains underexplored. In this review we summarize insights into how TME stressors such as hypoxia, nutrient competition, and metabolic byproducts subvert mitochondrial dynamics, redox balance, and mitochondrial DNA (mtDNA) signaling in T cells, natural killer (NK) cells, and macrophages, thereby directly impairing their antitumor efficacy. We emphasize that the restoration of mitochondrial fitness in immune cells, achieved by targeting metabolites in the TME and mitochondrial quality control, represents a pivotal axis for adoptive cell therapies (ACTs) and TME reprogramming.

Keywords: ROS; chimeric antigen receptor (CAR); metabolism; mitochondria; tumor immunotherapy

DOI: https://doi.org/10.1016/j.trecan.2025.08.006

bioRxiv. 2025 Sep 04. pii: 2025.09.01.673389. [Epub ahead of print]

An Inflammatory and Quiescent HSC Subpopulation Expands with Age in Humans.

Ksenia R Safina, Dylan A Kotliar, Michelle Curtis, Jonathan D Good, Chen Weng, Shawn David, Soumya Raychaudhuri, Antonia Kreso, Jennifer Trowbridge, Vijay G Sankaran, Peter van Galen.

Aging of the blood system impacts systemic health and can be traced to hematopoietic stem cells (HSCs). Despite multiple reports on human HSC aging, a unified map detailing their molecular age-related changes is lacking. We developed a consensus map of gene expression in HSCs by integrating seven single-cell datasets. This map revealed previously unappreciated heterogeneity within the HSC population. It also links inflammatory pathway activation (TNF/NFκB, AP-1) and quiescence within a single gene expression program. This program dominates an inflammatory HSC subpopulation that increases with age, highlighting a potential target for further experimental studies and anti-aging interventions.

DOI: https://doi.org/10.1101/2025.09.01.673389