bims-mithem 2025-10-12 papers

Issue of 2025–10–12
five papers selected by
Tim van Tienhoven, Erasmus Medical Center

Blood. 2025 Oct 07. pii: blood.2024026505. [Epub ahead of print]

A Notch trans-activation to cis-inhibition switch underlies hematopoietic stem cell aging.

Francesca Matteini, Roshana Thambyrajah, Sara Montserrat-Vazquez, Sascha Jung, Alba Ferrer-Perez, Patricia Herrero Molinero, Dina El Jaramany, Javier Lozano-Bartolomé, Eva Mejia-Ramirez, Jessica Gonzalez Miranda, Antonio Del Sol, Anna Bigas, Maria Carolina Florian.

Aged hematopoietic stem cells (HSCs) expand in clusters over time, while reducing their regenerative capacity and their ability to preserve the homeostasis of the hematopoietic system. The expression of Notch ligands in the bone marrow (BM) niche is essential for hematopoiesis. However, the impact of Notch signaling for adult HSC function and its involvement in HSC aging remains controversial. Here we show that Notch activation in young HSCs is not homogeneous, and it is triggered by sinusoidal expression of the Notch ligand Jagged2 (Jag2). Sinusoidal Jag2 deletion in young mice recapitulates the decrease in Notch activity observed in aged HSCs and alters HSC divisional symmetry and fate priming, promoting myeloid-biased HSCs (My-HSCs) expansion. Mechanistically, our data reveals that upon decreasing sinusoidal Jag2 expression, HSCs themselves upregulate Jag2, which cis-inhibits Notch signaling, resulting in the expansion of My-HSCs and in reduced hematopoietic regeneration. Collectively, these findings identify the crosstalk between BM niche-driven and HSC intrinsic features in regulating HSC fate priming and regenerative potential and reveal an extrinsic Notch trans-activation to intrinsic cis-inhibition switch underlying HSC aging.

DOI: https://doi.org/10.1182/blood.2024026505

Cancer Sci. 2025 Oct 11.

Heterogeneity of Cellular Senescence: Subtype-Specific Mechanisms and the Emerging Role of Plasma Membrane Damage.

Enaam Alghamdi, Keiko Kono.

Cellular senescence is a state of stable cell cycle arrest accompanied by heightened immune activity, contributing to aging and age-related diseases. Although once regarded as a terminal and static condition, cellular senescence is now recognized as a dynamic and highly regulated process controlled by complex molecular networks. In vitro, it can be triggered by a variety of stimuli, including telomere attrition, DNA damage, oncogene activation, mitochondrial dysfunction, and others. However, the precise in vivo triggers of cellular senescence remain unclear. Recent findings from our group demonstrate that plasma membrane damage can induce cellular senescence in cultured normal human fibroblasts. Notably, the gene expression profile of these cells shares key characteristics with the cells localized near fibrotic cutaneous wounds in humans. In this review, we highlight recent advances in understanding the diverse subtypes of cellular senescence and their underlying regulatory networks, their context-dependent roles in tumorigenesis, and the therapeutic potential and challenges associated with targeting senescent cells. Unraveling the heterogeneity of cellular senescence holds promise for harnessing the beneficial roles of cellular senescence while mitigating its pro-tumorigenic and pro-aging effects.

Keywords: cellular senescence; oncogene‐induced senescence; p16; p53; plasma membrane damage

DOI: https://doi.org/10.1111/cas.70223

FEBS Open Bio. 2025 Oct 10.

Mitochondria-associated membranes (MAMs): molecular organization, cellular functions, and their role in health and disease.

Viet Bui, Maryline Santerre, Natalia Shcherbik, Bassel E Sawaya.

Mitochondria-associated membranes (MAMs) are specialized contact sites between the endoplasmic reticulum (ER) and mitochondria that maintain cellular homeostasis through precisely orchestrated molecular mechanisms. These dynamic interfaces are maintained at 10-50 nm distances by complex tethering proteins, including the core IP3R-GRP7 5-VDAC1 complex and regulatory proteins, such as the sigma-1 receptor. MAMs coordinate multiple essential cellular processes: lipid synthesis and transfer, calcium signaling, metabolic regulation, and quality control through autophagy and mitophagy. Recent advances in super-resolution microscopy and proteomics have revealed that MAM dysfunction drives pathogenesis across various diseases. In Alzheimer's disease, disrupted MAM spacing directly affects Aβ production and mitochondrial function, while in Parkinson's disease, α-synuclein accumulation at MAMs impairs phosphatidylserine metabolism and mitochondrial dynamics. Beyond neurodegeneration, MAMs play crucial roles in metabolic disorders, cancer progression, and viral infections. This review provides mechanistic insights into MAM biology, from molecular organization to disease pathogenesis, integrating structural analyses with dynamic visualization approaches. We examine emerging therapeutic strategies targeting MAM-associated pathways and highlight their potential in treating complex diseases.

Keywords: ER–mitochondria contact sites; calcium signaling; cellular stress responses; lipid metabolism; mitochondria‐associated membranes; neurodegeneration

DOI: https://doi.org/10.1002/2211-5463.70121

Stem Cells. 2025 Oct 09. pii: sxaf065. [Epub ahead of print]

Novel strategies to expand and engineer hematopoietic stem cells.

Bailey R Klein, Angella Blake, Ritisha Rashmil, Amar B Desai.

Hematopoietic stem cell (HSC) transplantation is a lifesaving therapy for hematologic diseases, but its broader application remains constrained by challenges in sourcing, manipulating, and reliably expanding functional HSCs. In this review, we discuss strategies to expand and engineer HSCs by recreating essential aspects of the bone marrow niche. These include defined cytokine cocktails, small molecule modulators, stromal co-culture systems, and biomaterials that promote self-renewal while limiting differentiation. We highlight advances in three-dimensional organoid models and microfluidic platforms that better support long-term repopulating cells and reflect native microenvironments. In parallel, progress in gene delivery platforms, including both viral and nonviral approaches, is enabling more efficient and targeted modification of HSCs for therapeutic use in genetic disorders such as sickle cell disease and β-thalassemia. While these tools have advanced significantly, significant hurdles remain in scaling, preserving stem cell identity, and reducing culture-induced stress. Continued refinement of biomimetic systems and genome engineering technologies will be central to expanding the clinical utility of HSC-based therapies.

Keywords: Hematopoietic stem cells; biomaterials; gene therapy; niche engineering; stem cell expansion

DOI: https://doi.org/10.1093/stmcls/sxaf065