Biology subjects

Ellison-Hughes, G. M.

Publications and source records attributed to Ellison-Hughes, G. M..

4 recordsLinked to original sources

bioRxiv2026

Robust Myocardial Regeneration After Selective Cardiomyocyte Loss Is Driven by Cardiac Stem Cell Activation Through the miR-221-p57 Axis

A central unresolved and highly contested question in cardiac biology is whether the adult mammalian heart, believed to have a very limited endogenous cardiomyocyte (CM) regenerative capacity, can be coaxed into an effective regenerative response after acute CM loss. Using TgMyh6MCM:R26stop-DTA mice, we show that selective diffuse ablation of [~]15% of left ventricular CMs causes acute heart failure but is followed by complete structural and functional recovery within 28 days. Recovery is accomplished by robust generation of new mononucleated CMs, replacing [~]1/10 of the left ventricular CM compartment. This CM regeneration is produced by the activation of resident cardiac stem cells (CSCs), which exit quiescence, proliferate, produce new CMs, and subsequently return to quiescence. Depletion of the putative CSCs blocks repair, whereas transplantation of either clonogenic or primary CSCs through the systemic circulation fully restores myocardial regeneration and function, establishing that the CSCs home, nest and differentiate in the damaged myocardium and, therefore, are the main effectors of regeneration in this setting. Mechanistically, we show that miR-221-dependent repression of p57 governs the transition from quiescence--to activation--to differentiation--to quiescence of the CSCs, defining a reversible regulatory program which, under the proper conditions, endows the adult myocardium with robust CM regenerative competence.

cell biology↗

bioRxiv2022

Exercise induces myonuclear remodelling in humans independently of age

Age-related decline in skeletal muscle structure and function can be mitigated by regular exercise. However, the precise mechanisms that govern this are not fully understood. The nucleus plays an active role in translating forces into biochemical signals (mechanotransduction), with nuclear lamina protein Lamin A regulating nuclear shape, nuclear mechanics, and ultimately gene expression. Defective Lamin A expression causes muscle pathologies and premature ageing syndromes, but the roles of nuclear structure and function in physiological ageing and in exercise adaptations remain obscure. Here, we isolated single muscle fibres and carried out detailed morphological and functional analyses on myonuclei from young and older exercise-trained individuals. Strikingly, myonuclei from trained individuals were more spherical, less deformable, and contained a thicker nuclear lamina than untrained individuals. Complementary to this, exercise resulted in increased levels of Lamin A and increased myonuclear stiffness in mice. We conclude that exercise is associated with myonuclear remodelling, independently of age, which may contribute to the preservative effects of exercise on muscle function throughout the lifespan. Key pointsO_LIThe nucleus plays an active role in translating forces into biochemical signals C_LIO_LIMyonuclear aberrations in a group of muscular dystrophies called laminopathies suggest that the shape and mechanical properties of myonuclei are important for maintaining muscle function. C_LIO_LIHere, we present striking differences in myonuclear shape and mechanics associated with exercise, in both young and old humans. C_LIO_LIMyonuclei from trained individuals were more spherical, less deformable, and contained a thicker nuclear lamina than untrained individuals. C_LIO_LIWe conclude that exercise is associated with age-independent myonuclear remodelling, which may help to maintain muscle function throughout the lifespan. C_LI

cell biology↗

bioRxiv2021

Imatinib mesylate induces necroptotic cell death and impairs autophagic flux in human cardiac progenitor cells

The receptor tyrosine kinase inhibitor imatinib mesylate has improved patient cancer survival rates but has been linked to long-term cardiotoxicity. This study investigated the effects of imatinib on cell viability, apoptosis, autophagy and necroptosis in human cardiac progenitor cells in vitro. After 24 hours, imatinib significantly reduced cell viability (75.9{+/-}2.7% vs._100.0{+/-}0.0%, n=5, p<0.05) at concentrations comparable to peak plasma levels (10 {micro}M). Further investigation showed no increase in caspase 3 or 7 activation. Imatinib also significantly reduced the fluorescence of cells stained with TMRM (74.6{+/-}6.5% vs. 100.0{+/-}0.0%, n=5, p<0.05), consistent with mitochondrial depolarization. Imatinib increased lysosome and autophagosome content relative to the control, as indicated by changes in acridine orange fluorescence (46.0{+/-}5.4% vs. 9.0{+/-}3.0, n=7, p<0.001) and expression of LAMP2 (2.4{+/-}0.3 fold, n=3, p<0.05) after 24 hours treatment. Although imatinib increased the expression of proteins associated with autophagy, it also impaired the autophagic flux, as demonstrated by the proximity ligation assay staining for LAMP2 (lysosome marker) and LC3II (autophagosome marker), with control cells showing 11.3{+/-}2.1 puncta per cell and 48 hours of imatinib treatment reducing the visible puncta to 2.7{+/-}0.7 per cell (n=10, p<0.05). Cell viability was partially recovered by autophagosome inhibition by wortmannin, with a 91.8{+/-}8.2% (n=5, p>0.05) increase in viability after imatinib and wortmannin co-treatment. Imatinib-induced necroptosis was associated with an 8.5{+/-}2.5-fold increase in activation of mixed lineage kinase domain-like pseudokinase. Imatinib-induced toxicity was rescued by RIP1 inhibition relative to the control; 88.6{+/-}3.0% vs. 100.0{+/-}0.0% (n=4, p>0.05). In summary, imatinib applied to human cardiac progenitor cells depolarizes mitochondria and induces cell death through necroptosis, which can be recovered by inhibition of RIP1, with an additional partial role for autophagy in the cell death pathway. These data provide two possible targets for co-therapies to address imatinib-induced long-term cardiotoxicity.

pharmacology and toxicology↗

bioRxiv2018

Senescent, dysfunctional human cardiac progenitor cells (CPCs) accumulate in the aged heart and elimination of senescent cells enhances CPC activation and cardiomyocyte proliferation in aged mice

Aging leads to increased cellular senescence and is associated with decreased potency of tissue-specific stem/progenitor cells. Here we have done an extensive analysis of cardiac progenitor cells (CPCs) isolated from human subjects with cardiovascular disease (n=119), aged 32-86 years. In aged subjects (>74 years old) over half of CPCs are senescent (p16INK4A, SA-{beta}-gal, DNA damage {gamma}H2AX, telomere length, Senescence-Associated Secretory Phenotype (SASP)), unable to replicate, differentiate, regenerate or restore cardiac function following transplantation into the infarcted heart. SASP factors secreted by senescent CPCs renders otherwise healthy CPCs to senescence. Elimination of senescent CPCs using senolytics abrogates the SASP and its debilitative effect in vitro. Global elimination of senescent cells in aged mice (INK-ATTAC or wildtype mice treated with D+Q senolytics) in vivo activates resident CPCs (0.23{+/-}0.06% vs. 0.01{+/-}0.01% vehicle; p<0.05) and increased the number of small, proliferating Ki67-, EdU-positive cardiomyocytes (0.25{+/-}0.07% vs. 0.03{+/-}0.03% vehicle; p<0.05). Therapeutic approaches that eliminate senescent cells may alleviate cardiac deterioration with aging and rejuvenate the regenerative capacity of the heart.

physiology↗