Understanding ROS signaling and evolution during animal regeneration offers promising opportunities for novel therapeutic approaches

Résumé :

Despite their potentially harmful oxidative properties, Reactive Oxygen Species (ROS) have been harnessed by living organisms during evolution as signaling molecules involved in various physiological processes. In the past fifteen years, they have been recognized across metazoans—from cnidarians to vertebrates—as consistent actors of restorative regeneration, the process by which organisms rebuild lost body parts. This discovery suggests that ROS could represent a conserved mechanism underlying regeneration and a valuable target to enhance regenerative capacity in poorly regenerating species such as humans. Yet, growing evidence shows that the regulatory roles and modes of action of ROS vary considerably among species. Consequently, it appears necessary to continue studying the involvement of ROS in the regenerative process of various species, to distinguish between common and species-specific mechanisms. Such knowledge could offer perspective as to how ROS came to be involved in the regenerative process of different metazoan species during evolution and, more broadly, how they fit into the still unresolved evolutionary history of regeneration. In addition, by enabling us to better understand why some species regenerate better than others, and how their regenerative capacities may have changed during evolution, we argue that such studies will help identify new avenues in regenerative medicine. In this review, we synthesise the literature evidencing the involvement and requirement of ROS during regeneration in various species and structures, identifying major knowledge gaps, and we highlight the need for further thorough investigation of the role of ROS in metazoan species for both evolutionary and therapeutic perspectives.

Vullien, A., John, J., Rampon, C., Amaya, E., Röttinger, E., & Gazave, E. (2026). Understanding ROS signaling and evolution during animal regeneration offers promising opportunities for novel therapeutic approaches. Cellular and Molecular Life Sciences.

The Identity of Stem Cell Kinds

Résumé :

Stem cells are defined by their self-renewal and differentiation abilities. Through those properties, they ensure the production and renewal of organisms’ cells and, in some species, the regeneration of lost parts, making them a key element of biology. Although they share a same function and definition, there is a wide diversity across stem cells, reflected by the fact that stem cells are categorized into various types and subtypes. This diversity among stem cells raises a key philosophical question: Do stem cells belong to a natural kind? Claims and arguments made by biologists and philosophers, far from converging toward a consensual response, highlight the need for more (interdisciplinary) investigation to advance this question. In response to this challenge, we explore the hypothesis that a phylogenetic approach may offer a productive framework for addressing these conceptual tensions. After describing the strengths and limitations of such a strategy, we discuss how it can advance fields like regenerative medicine and cancer therapies by clarifying stem cell diversity and improving therapeutic strategies.

Guglielmo Militello, Louis Pare, Eve Gazave, Lucie Laplane. The Identity of Stem Cell Kinds. British Journal for the Philosophy of Science, 2026, ⟨10.1086/743816⟩

Estrogen Receptor Beta Isoforms Interplay Integrates Nuclear and Extra-Nuclear Signaling to Modulate Human Granulosa Cell Growth

Résumé :

Estradiol (E2) regulates ovarian follicular development and granulosa cell (GC) function primarily through estrogen receptor β (ERβ). Human GCs express several ERβ isoforms, including ERβ1, ERβ2, ERβ4, and ERβ5, but how their relative abundance modulates estrogen signaling remains unclear. Here, we investigated the contribution of nuclear and extra-nuclear ERβ signaling to human GC growth and function. HGrC1 granulosa cells lacking endogenous estrogen receptors were engineered to stably express individual or combined ERβ isoforms. Functional analyses showed that ERβ1 and ERβ4 inhibited GC proliferation, whereas ERβ2 and ERβ5 promoted cell growth. Co-expression of all isoforms resulted in an overall inhibitory effect, indicating that GC responses depend on ERβ isoform balance rather than a single receptor. Reporter assays demonstrated that only ERβ1 activated estrogen response element-dependent transcription, while the other isoforms suppressed E2-dependent ERα transactivation. In contrast, ERβ2, ERβ4, and ERβ5 activated AP-1 signaling in a ligand-independent manner and attenuated ERβ1-mediated repression, identifying AP-1 as a central node of ERβ isoform crosstalk. RNA sequencing following selective ERβ1 depletion in primary human granulosa lutein cells revealed that ERβ1 is required for E2 responsiveness and regulates genes involved in membrane potential, ion transport, and cytoskeletal organization. Proteomic and biochemical analyses further identified isoform-specific signaling networks involving ERK1/2, Akt, and CaMKII pathways. Together, these findings demonstrate that ERβ isoform balance orchestrates estrogen signaling through coordinated nuclear and extra-nuclear mechanisms controlling GC growth and function.

Marie C, Baskaran IN, Corre R, Mayeur A, Grynberg M, Chevreux G, L’Hôte D, Cohen-Tannoudji J, Chauvin S. Estrogen Receptor Beta Isoforms Interplay Integrates Nuclear and Extra-Nuclear Signaling to Modulate Human Granulosa Cell Growth. FASEB J. 2026 Oct 15;40(19):e72328. doi: 10.1096/fj.202602705RR. PMID: 42827403; PMCID: PMC13633505.

A structural model for the autoinhibition of the γ-TuRC–activating CM1 domain

Résumé :

Microtubule nucleation by γ-tubulin ring complexes (γ-TuRCs) must be spatiotemporally controlled to avoid major cell division errors. γ-TuRCs are activated by the centrosome-specific binding of a highly conserved centrosomin motif 1 (CM1) domain, but how binding is prevented in the cytosol remains unclear. We provide the first structural explanation for CM1 autoinhibition, revealing that stable intramolecular interactions mediate cooperative folding to block γ-TuRC–binding interfaces. Using various structural approaches, we show that CM1 forms a conserved dimeric coiled-coil hairpin that sequesters a key phenylalanine residue essential for γ-TuRC binding. This appears sufficient for autoinhibition in humans, but in flies autoinhibition requires the association of an upstream CM1 autoinhibition (CAI) domain, which forms a 4-helix dimer that covers the opposite phenylalanine residue of the hairpin dimer. Collectively, the data provide the first structural model for CM1 autoinhibition and reveal evolutionary differences across species.

Elfarkouchi A, Vitard A, Mammri L, Brier S, Tanneur L, Hu C, Thureau A, Joly N, Ochsenbein F, Conduit PT. A structural model for the autoinhibition of the γ-TuRC-activating CM1 domain. J Cell Biol. 2026 Nov 2;225(11):e202605160. doi: 10.1083/jcb.202605160. Epub 2026 Sep 30. PMID: 42814412.

A principal-stress rule for cell division in epithelia

Résumé :

Dense active materials must continuously relieve internal mechanical stress to remain structurally stable as they are driven far from equilibrium. In epithelial tissues, this relief occurs through cell division, where, according to Hertwig’s century-old rule, cells divide along their long axis. We show that as epithelia densify, this geometric rule is superseded by a mechanical one: cells divide along the principal axis of anisotropic stress, independently of the isotropic stress state. Using direct force measurements and stress inference, we demonstrate that stress orientation governs division across mechanically distinct systems, from fluid-like to jammed monolayers and structurally heterogeneous organoids, remaining predictive where cell shape fails. This stress-oriented remodeling is reciprocally coupled to the material’s mechanical state: anisotropic stress accelerates cell-cycle progression, while division locally dissipates it, closing a negative feedback loop. This “principal-stress rule” provides a general mechanical framework linking internal stress, structural remodeling and homeostasis in living materials.

Anger, L., Ma, T., Wodrascka, F. et al. A principal-stress rule for cell division in epithelia. Nat Commun (2026). https://doi.org/10.1038/s41467-026-77813-5

Bacterial growth under confinement requires transcriptional adaptation to resist turgor pressure build-up

Résumé :

Bacterial proliferation in confined spaces occurs in biofilms, intracellular compartments, or infection sites, generating mechanical constraints. We investigated how growth-induced mechanical pressure affects bacterial physiology using a microfluidic device ensuring nutrient access. We found that proliferating Escherichia coli cells generate forces in the hundreds of kPa range decoupling growth and division, producing shorter bacteria. Increased cytoplasmic protein concentrations and crowding induce division arrest and decreased protein synthesis. In contrast, growth-induced pressure keeps increasing during confinement. Theoretical modeling predicts this novel regime of steady pressure increase, termed overpressurization, driven by persistent metabolite synthesis. Under confinement, the Rcs pathway is activated, and rcs mutants display abnormal shapes only in the overpressurized state. Therefore, transcriptional adaptation is required to resist pressure build-up. A uropathogenic strain displayed the same confined growth phenotypes in vitro, highlighting the potential relevance of these pressurized regimes during infection.

Le Blanc, L., Alric, B., Rollin, R., Xénard, L., Avdovic, M., Goussard, S., Mazenq, L., Piel, M., Tinevez, J.-Y., Delarue, M., Duménil, G., & Bonazzi, D. (2026). Bacterial growth under confinement requires transcriptional adaptation to resist turgor pressure build-up. Nature Communications. https://doi.org/10.1038/s41467-026-76492-6

Extracellular-matrix mediated stresses spatially bias myoblast fusion and myotube growth

Résumé :

Myoblast fusion into multinucleated myotubes is essential for skeletal muscle development and repair, yet how tissue-scale mechanics contributes to this process remains poorly understood. Here, we show that primary myoblasts behave as an evolving active nematic system in which actomyosin-dependent stresses, extracellular-matrix (ECM) remodeling and fusion-driven myotube growth are dynamically coupled. As myoblasts fuse into elongated myotubes, orientational order increases and the nematic field is progressively reshaped. We identify a strong coupling between cellular and ECM nematic organization, whereby cytoskeleton-dependent ECM remodeling stabilizes topological defects and reinforces their associated stress patterns. Fusion events preferentially accumulate near comet-shaped +1/2 defects, which correspond to regions of high compressive stress predicted by our theoretical model. Our findings support a model in which the intrinsic fusion machinery provides fusion competence, while ECM-stabilized nematic stress patterns spatially bias the localization of fusion events. Fusion-driven myotube growth then feeds back on the mechanical landscape, increasing nematogen length and stress magnitude. Together, these results reveal a self-reinforcing biomechanical mechanism that contributes to the organization of myoblast fusion and myotube growth, with potential relevance for developmental and regenerative morphogenesis.

Le Toquin Y, Dubey S, Ardaševa A, Balasubramaniam L, Delaune E, Morin V, Doostmohammadi A, Marcelle C, Ladoux B. Extracellular-matrix mediated stresses spatially bias myoblast fusion and myotube growth. Nat Commun. 2026 Aug 22;17(1):10057. doi: 10.1038/s41467-026-76967-6. PMID: 42768042; PMCID: PMC13594122.

The mechanistic and evolutionary diversity of programmed DNA elimination

Résumé :

Beyond somatic mutations, the genetic makeup of an organism is often assumed to remain constant across all cells or nuclei within individuals. However, some organisms exhibit programmed DNA elimination (PDE), whereby specific cell lineages lose DNA segments or whole chromosomes. Building evidence indicates that PDE occurs in a wide range of eukaryotes and is linked to diverse cellular processes including gene silencing, germline differentiation, genome defence and sex determination. Here we compare PDE across broad phylogenetic groups, highlighting the mechanistic diversity, overlooked plasticity in genome integrity and the considerable gaps in our understanding of why PDE emerged recurrently and is maintained across the Tree of Life.

Duharcourt S*, Ross L*, Suh A*, Dedukh D, Delattre M, Houben A, Kokko H, Reifova R, Richard Albert J, Roze D, Smith JJ, Wang J.Nat Rev Genet. 2026 Sep 8. doi: 10.1038/s41576-026-01004-7. PMID: 42711411 Review.

Nonlinearities and Switch-Like Behavior in Gene Expression: From Genetics to Biochemistry and Back.

Résumé :

Many developmental and physiological outcomes depend on transcriptional thresholds or switches. The transcriptional output, ultimately measured as mature RNA, is determined by a series of molecular steps that can introduce thresholds, bottlenecks, or amplification mechanisms. Their combination can convert quantitative changes in regulator abundance into more-than-proportional changes in mature RNA production. Such nonlinear, S-shaped/sigmoidal input-output relationships may account, at least in part, for the haploinsufficiency (HI) of transcription factors (TFs) and chromatin regulators. Here, we link genetic evidence for dosage sensitivity to biochemical nonlinearity in the context of transcription regulation. Without aiming to be exhaustive, we discuss several sources of sigmoidicity, such as classical cooperative DNA binding and transcriptional synergy. We also analyze how chromatin factors, three-dimensional nuclear organization, and transcriptional condensates can generate thresholds. In addition, we explore the roles of epigenetic hysteresis and molecular memory. Finally, at the systems level, we consider how nonlinearities can emerge from regulatory networks that convert graded changes in regulator abundance into stable alternative states. Overall, this paper supports the view that HI of TFs and chromatin regulators does not rely on a single mechanism. Rather, HI is a phenotypic consequence of the disruption of diverse molecular and network architectures that translate dosage perturbations into discrete biochemical and phenotypic outcomes.

Veitia RA, Birchler JA. Nonlinearities and Switch-Like Behavior in Gene Expression: From Genetics to Biochemistry and Back. FASEB J. 2026 Aug 31;40(16):e72232. doi: 10.1096/fj.202603153R. PMID: 42631548; PMCID: PMC13499265.

Ploidy-dependent modulation of DNA replication kinetics in Xenopus

Résumé : An important question in cell biology is how DNA replication programs scale with genome size following polyploidization, an evolutionary process that increases DNA content without proportionally extending the cell cycle duration. In particular, comparative analyses across closely related polyploid species are lacking. Here, we developed an interspecies in vitro replication system using Xenopus laevis egg extracts and sperm nuclei from three closely related Xenopus species with distinct ploidy levels: diploid (Xenopus tropicalis), tetraploid (Xenopus laevis), and dodecaploid (Xenopus eysoole). Replication in diploid nuclei was faster than in tetraploid nuclei, consistent with higher fork density and speed, as expected. Counterintuitively, replication in dodecaploid nuclei was also accelerated relative to tetraploid nuclei, indicating that increased ploidy does not necessarily prolong S phase. Given the high conservation of replication genes, our results suggest that replication programs are dynamically tuned across polyploid species, revealing an unexpected flexibility in how eukaryotic cells adapt DNA replication to large-scale genome expansion.

Narassimprakash H, Haccard O, Li Z, Pollet N, Marheineke K. Ploidy-dependent modulation of DNA replication kinetics in Xenopus. FEBS J. 2026 Aug 18. doi: 10.1111/febs.70703. Epub ahead of print. PMID: 42609175.