Biology subjects

Knoch, J.

Publications and source records attributed to Knoch, J..

5 recordsLinked to original sources

bioRxiv2026

Dormancy, not apoptosis, restricts hematopoietic stem cell mutagenesis during aging

Genome instability and mutagenesis are hallmarks of aging, acting as drivers of some age-associated pathologies, including cancer1-3. Somatic cells engage multiple layers of protection against mutagenesis, including detoxification of genotoxic metabolites; repair of DNA damage; and elimination of cells which suffer excessive damage4-7. In this context, the intrinsic apoptotic pathway is engaged in response to activation of the DNA damage response (DDR) and is thought to play a major role in limiting accumulation of mutations, particularly in cells that act as an origin for cancer, such as somatic stem cells8,9. However, the dissection of the relative contribution of different protective mechanisms that restrict mutagenesis in such cells is confounded by the long time frame of experiments; relatively low mutation burden in non-malignant cells; and high variance across individuals due to differences in germ line and environment. Here we employ deep whole-genome sequencing (WGS) combined with extended time-course sampling from a range of experimental mouse models to study mutation acquisition in hematopoietic stem cells (HSCs) during aging. Having validated that murine HSCs recapitulate mutation acquisition patterns observed in aged human HSCs, we made the surprising discovery that apoptosis has a negligible role in restricting mutagenesis. Instead, we found that HSC dormancy inhibits mutagenesis during normal aging, with dormant HSCs from old mice demonstrating a mutation burden akin to their young counterparts. Importantly, breaking HSC dormancy via induction of sterile inflammation led to a dramatic acceleration in mutation rate, demonstrating that non-genotoxic environmental stimuli can modulate genome stability. These findings provide new insights into the correlation between inflammation and both aging and carcinogenesis.

cell biology↗

bioRxiv2025

Neuronal and Astrocytic Activity Changes Induced by Acute and Chronic Stress

Exposure to acute, repeated, or chronic stress elicits a spectrum of cellular changes ranging from adaptive to maladaptive, including in the prefrontal cortex (PFC) where both neurons and astroglia undergo morphological, cellular and molecular remodeling. However, whether these alterations translate into altered cell activity and neuron-astroglia communication and how such changes evolve with recurrent stress or chronic stress exposure remains poorly understood. To address these questions, we used dual-color in vivo fiber photometry to longitudinally record PFC neuronal and astroglial calcium (Ca{superscript 2}) signals in the same mice during a brief (tail pinch), sustained (immobilization) acute stress, repeated homotypic stress across weeks, and unpredictable chronic mild stress (UCMS), tracking of same cellular network across time. We found that acute stressors elicited coordinated increases in neuronal and astroglial Ca{superscript 2} activity and enhanced their Ca2+ signal coupling. Repeated intermittent stress induced comparable per-cell-type responses but progressively strengthened coupling, suggesting adaptation. We also demonstrated that this trajectory is reversed under UCMS; neuronal Ca{superscript 2} reactivity to stress challenge was sensitized whereas astroglial reactivity was blunted. This was associated with a weakened intercellular coupling (-3.5 fold) and astroglia became progressively hyporesponsive to neuronal drive. UCMS-induced neuron-astroglia functional coupling impairment coincided with the onset of anhedonia- and anxiety-like behavioral deficits. These findings position impaired neuron-astroglial functional coupling as a potential substrate of stress-induced cortical dysfunction that may distinguish adaptive from maladaptive stress responses, offering a mechanistically tractable target for intervention in stress-related psychiatric disease such as depression, where dysfunction in both cell types has been consistently reported.

neuroscience↗

bioRxiv2025

A kinetics-based model of hematopoiesis reveals extrinsic regulation of skewed lineage output from stem cells

Residing at the top of the hematopoietic hierarchy, long-term hematopoietic stem cells (HSCs) are capable of self-renewal and sustained blood cell regeneration. Over the past decades, single-cell and clonal analyses have revealed substantial functional and molecular heterogeneity within this compartment, challenging the notion that self-renewal is inherently tied to balanced, multi-lineage blood production. However, a cohesive model that explains the relationships among these diverse HSC states remains elusive. Here, we combined single-cell transplantations of over 1,000 highly purified murine long-term HSCs with in-depth phenotyping of their clonal progeny to achieve a detailed, time-resolved understanding of heterogeneous reconstitution outcomes. We identified reconstitution kinetics as an overall unifying metric of HSC functional potency, with the most potent HSCs displaying the greatest delay in hematopoietic reconstitution. Importantly, a progressive acceleration in reconstitution kinetics was also associated with a gradual shift in mature cell production from platelet and erythro-myeloid bias to balanced, and eventually lymphoid bias. Serial single-cell transplantations of HSCs revealed a unidirectional acceleration in reconstitution kinetics accompanied by a gradual decline in functional potency of daughter HSCs, aligning diverse phenotypes along a linear hierarchical trajectory. Mathematical modeling, together with experimental modulation of lineage-biased blood production, demonstrated that apparent lineage biases actually arise from cell-extrinsic feedback regulation and clonal competition between slow- and fast-engrafting clones to occupy the limited compartment sizes of mature lineages. Our study reconciles multiple layers of HSC heterogeneity into a unifying framework, prompting a reevaluation of the meaning of lineage biases in both normal and diseased hematopoiesis, with broad implications for other regenerating tissues during development, homeostasis, and repair.

cell biology↗

bioRxiv2021

Dynamic behavioral and molecular changes induced by chronic stress exposure in mice

Depression is a leading cause of disabilities around the world, and the underlying mechanisms involved in its pathophysiology are broad and complex. Exposure to chronic stress is a risk factor for developing depressive-symptoms and contributes to cellular and molecular changes precipitating the emergence of symptoms. In the brain, excitatory neurons, inhibitory interneurons and supporting astroglial cells are all sensitive to chronic stress exposure and are known to be impaired in depression. Using an animal model of chronic stress, we assessed the impact of variable durations of chronic stress on the emergence of behavioral deficits and associated molecular changes in the prefrontal cortex (PFC), brain region highly sensitive to stress and impaired in depression. Mice were exposed to up to 35 days of chronic restraint stress and were assessed weekly on behavioral tests measuring anxiety and anhedonia. PFC Protein and RNA levels of specific markers of excitatory, inhibitory synapses and astroglia were quantified using western blot and qPCR, respectively. Correlation and integrative network analyses were used to investigated the impact of chronic stress on the different compartments. Results showed that chronic stress induces anxiety-like behaviors within 7 days, while anhedonia-like behaviors were observed only after 35 days. At the molecular level, alterations of many markers were observed, in particular with longer exposure to chronic stress. Finally, correlation analyses and integrative network analyses revealed that male and female mice react differently to chronic stress exposure and that some markers seem to be more correlated to behaviors deficits in males than in females. Our study demonstrate that chronic induces a dynamic changes that can be observed at the behavioral and molecular levels, and that male and female mice, while exhibiting similar symptoms, have different underlying pathologies.

neuroscience↗

bioRxiv2020

Hematopoietic stem cells fail to regenerate following inflammatory challenge.

Hematopoietic stem cells (HSCs) are canonically defined by their capacity to maintain the HSC pool via self-renewal divisions. However, accumulating evidence suggests that HSC function is instead preserved by sustaining long-term quiescence. Here, we study the kinetics of HSC recovery in mice, following an inflammatory challenge that induces HSCs to exit dormancy. Repeated inflammatory challenge resulted in a progressive depletion of functional HSCs, with no sign of later recovery. Underlying this observation, label retention experiments demonstrated that self-renewal divisions were absent or extremely rare during challenge, as well as during any subsequent recovery period. While depletion of functional HSCs held no immediate consequences, young mice exposed to inflammatory challenge developed blood and bone marrow hypocellularity in old age, similar to elderly humans. The progressive, irreversible attrition of HSC function demonstrates that discreet instances of inflammatory stress can have an irreversible and therefore cumulative impact on HSC function, even when separated by several months. These findings have important implications for our understanding of the role of inflammation as a mediator of dysfunctional tissue maintenance and regeneration during ageing.

cell biology↗