bims-raghud 2025-05-04 papers

Issue of 2025–05–04
three papers selected by
Irene Sambri, TIGEM

Aging Cell. 2025 May 01. e70083

TFEB Orchestrates Stress Recovery and Paves the Way for Senescence Induction in Human Dermal Fibroblasts.

Lena Guerrero-Navarro, Pablo Monfort-Lanzas, Vinzenz Krichbaumer, Mariana E G De Araújo, Jlenia Monfregola, Lukas A Huber, Andrea Ballabio, Pidder Jansen-Dürr, Maria Cavinato.

Cells experience oxidative stress and widespread cellular damage during stress-induced premature senescence (SIPS). Senescent cells show an increase in lysosomal content, which may contribute to mitigating cellular damage by promoting autophagy. This study investigates the dynamics of lysosomal quality control in human dermal fibroblasts (HDF), specifically examining lysosomal signaling pathways during oxidative stress-induced SIPS. Our results reveal distinct signaling responses between the initial stress phase and the ensuing senescent phenotype. During the stress phase, treatment with tBHP, which undermines the antioxidant response, leads to elevated reactive oxygen species (ROS) and lysosomal damage. ROS accumulation activates AMP-activated protein kinase (AMPK) and inhibits Akt, which correlates with the suppression of mammalian target of rapamycin (mTOR). Inactivation of mTOR during this phase aligns with the activation of transcription factor EB (TFEB), a key regulator of autophagy and lysosomal biogenesis. TFEB knockdown under stress increased apoptosis, highlighting the protective role of TFEB in the stress response. As cells transition to senescence, TFEB activity, required for the autophagic damage repair, becomes less critical. The decrease in ROS levels leads to the normalization of AMPK and Akt signaling, accompanied by the reactivation of mTOR. This reactivation of mTOR, which is critical for establishing the senescent state, is observed alongside the inactivation of TFEB. Consequently, as damage decreases, TFEB activity decreases. Our results suggest a dynamic interplay between TFEB and mTOR, highlighting a critical role of TFEB in ensuring cellular survival during SIPS induction but becoming dispensable once senescence is established.

Keywords: SIPS; TFEB; mTOR; senescence; tBHP

DOI: https://doi.org/10.1111/acel.70083

Methods Mol Biol. 2025 ;2924 93-100

A Robust Protocol for Pluripotent Stem Cell Modeling of 3D Chamber-Like Cardiac Organoids.

Michel Pucéat.

The formation of cardiac organoids brings a new 3D model of cardiac development. The organoid is also very helpful in screening drug efficiency or toxicity. Inspired by cardiac biology of development, a step-by-step protocol is described to generate cardiac chamber-like organoids from pluripotent stem cells. A few examples of functional tests and the use of these organoids for drug toxicity are reported.

Keywords: Cardiac development; Cardiogenesis; Drug screening; Heart; Organogenesis

DOI: https://doi.org/10.1007/978-1-0716-4530-7_7

Nature. 2025 Apr 30.

Selective inhibition of stromal mechanosensing suppresses cardiac fibrosis.

Matrix-derived biophysical cues are known to regulate the activation of fibroblasts and their subsequent transdifferentiation into myofibroblasts1-6, but whether modulation of these signals can suppress fibrosis in intact tissues remains unclear, particularly in the cardiovascular system7-10. Here we demonstrate across multiple scales that inhibition of matrix mechanosensing in persistently activated cardiac fibroblasts potentiates-in concert with soluble regulators of the TGFβ pathway-a robust transcriptomic, morphological and metabolic shift towards quiescence. By conducting a meta-analysis of public human and mouse single-cell sequencing datasets, we identify the focal-adhesion-associated tyrosine kinase SRC as a fibroblast-enriched mechanosensor that can be targeted selectively in stromal cells to mimic the effects of matrix softening in vivo. Pharmacological inhibition of SRC by saracatinib, coupled with TGFβ suppression, induces synergistic repression of key profibrotic gene programs in fibroblasts, characterized by a marked inhibition of the MRTF-SRF pathway, which is not seen after treatment with either drug alone. Importantly, the dual treatment alleviates contractile dysfunction in fibrotic engineered heart tissues and in a mouse model of heart failure. Our findings point to joint inhibition of SRC-mediated stromal mechanosensing and TGFβ signalling as a potential mechanotherapeutic strategy for treating cardiovascular fibrosis.

DOI: https://doi.org/10.1038/s41586-025-08945-9