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Azimi, I.

Publications and source records attributed to Azimi, I..

2 recordsLinked to original sources
bioRxiv2026

Ca2+-mediated protein citrullination regulates proliferation in the regenerating and malignant CNS

Unlike most adult mammals, regenerative vertebrates can awaken dormant neural stem cells in response to injury. Understanding how this process is regulated could guide strategies to activate stem cells for tissue repair and limit aberrant proliferation in cancers of the CNS. Here, using zebrafish injury models and high-speed live imaging, we identify hydrodynamically-activated Ca{superscript 2} signalling as a key driver of neural stem cell activation. Local injury-associated changes in CSF flow activate mechanoreceptors at the site of spinal cord lesions, triggering pulsatile Ca{superscript 2} activity and progenitor proliferation. We identify Ca{superscript 2}-regulated peptidylarginine deiminase enzymes (PADs) as key downstream effectors that citrullinate intracellular targets in a Ca{superscript 2}-dependent manner to drive progenitor activation. Finally, we show that PAD inhibitors suppress the growth of aggressive medulloblastoma cells in preclinical laboratory models. Together, these findings uncover a novel mechanism of proliferation control in the vertebrate CNS and highlight the value of regenerative studies for identifying therapeutic targets. Graphical Summary O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/701650v1_ufig1.gif" ALT="Figure 1"> View larger version (67K): org.highwire.dtl.DTLVardef@3b7a56org.highwire.dtl.DTLVardef@dcc81forg.highwire.dtl.DTLVardef@d6a208org.highwire.dtl.DTLVardef@127de86_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIDamage signals trigger changes in cilia activity and CSF flow to create a transient hydrodynamic niche at the site of spinal cord injuries. C_LIO_LISpecialised CSF-contacting neurons detect altered CSF circulation and initiate a signalling relay that culminates in elevated Ca{superscript 2} activity within dormant neural progenitors. C_LIO_LICa{superscript 2}-activated PAD enzymes link Ca{superscript 2} signalling to cell cycle progression by citrullinating intracellular targets in a Ca{superscript 2}-dependent manner. C_LIO_LIPAD inhibition suppresses medulloblastoma growth in preclinical laboratory models, revealing a conserved regulatory mechanism with translational potential. C_LI

neuroscience↗
bioRxiv2024

Single-cell fluorescence imaging reveals heterogeneity in senescence biomarkers and identifies rapamycin-responsive sub-populations

Cellular senescence is a state of irreversible cell cycle arrest accompanied by a distinctive inflammatory secretory profile known as the senescence-associated secretory phenotype (SASP). While various biomarkers, such as senescence-associated beta-galactosidase (SA-{beta}gal), EdU incorporation, P21, and P16, are used to identify senescent cells, no single biomarker universally defines cellular senescence, and current methods often fail to address heterogeneity in biomarker expression levels. This study leverages single-cell fluorescence imaging to assess multiple senescence markers including SA-{beta}gal enzymatic activity, P21 and IL-6 expression, and nuclear and cell area, in chemotherapy-induced (mitomycin C) and oxidative stress-induced (D-galactose) senescence models in human fibroblasts. Our findings reveal significant heterogeneity in SA-{beta}gal activity and distinct sub-populations within senescent cells. Nuclear and cell area measurements emerged as robust indicators of cellular senescence, displaying similar variability across individual cells. Importantly, we identified specific nuclear area sub-populations that strongly correlate with IL-6 expression levels, demonstrating a relationship between the heterogeneous expression of senescence biomarkers and the SASP. To address this heterogeneity, we introduced an induction threshold method to more accurately quantify the percentage of cells expressing senescence biomarkers. Furthermore, in both senescence models, we observed that rapamycin, a well-known senomorphic agent, selectively targets specific biomarker-expressing sub-populations. This study underscores the value of assessing cellular heterogeneity in senescence research and provides an improved approach for analysing senescence markers in diverse cellular contexts.

cell biology↗