Biology subjects

Hunter, Z.

Publications and source records attributed to Hunter, Z..

4 recordsLinked to original sources

bioRxiv2026

Characterization of Electrophysiological and Transcriptomic Alterations in Patient-Derived Neurons from CHAMP1 Syndrome

Mutations in chromosome alignment maintaining phosphoprotein 1 (CHAMP1) have been linked to neurodevelopmental disorders characterized by intellectual disability, developmental delay, and autism spectrum disorder. However, the cellular and electrophysiological mechanisms by which CHAMP1 mutations disrupt human neuronal development remain poorly understood. In the present study, we used patient-derived induced pluripotent stem cells (iPSCs) carrying two pathogenic CHAMP1 mutations and generated neural progenitor cells (NPCs) and excitatory neurons to investigate the effects of each mutation on neuronal maturation and function, DNA repair, and gene expression. Proliferative capacity declines with CHAMP1 dosage, while DNA repair dysfunction is allele-specific. Whole-cell patch-clamp electrophysiology revealed that CHAMP1 mutant neurons exhibit significant alterations in intrinsic membrane properties during early developmental stages, including depolarized resting membrane potential, reduced action potential firing, and impaired waveform kinetics. These functional deficits were accompanied by reduced sodium and potassium current densities, suggesting impaired ion channel accumulation during neuronal maturation. Furthermore, recordings of spontaneous excitatory postsynaptic currents indicated altered synaptic activity and reduced proportions of synaptically active neurons. Morphological analyses showed that CHAMP1-deficient neurons exhibit impaired neurite outgrowth and branching, supporting a defect in neuronal maturation. Single-nucleus transcriptomic profiling further revealed delayed developmental trajectories and mutation-specific dysregulation of synaptic gene programs enriched for autism, ADHD, and epilepsy risk genes. Together, these findings demonstrate that CHAMP1 mutations disrupt multiple aspects of neuronal development, including homologous recombination (HR) dysfunction in NPCs, membrane excitability, ion channel function, and synaptic connectivity. Our results provide insights into the neurobiological consequences of CHAMP1 mutations and establish patient-derived neurons as a platform to investigate cellular pathophysiology and potential therapeutic strategies for CHAMP1-associated neurodevelopmental disorders.

neuroscience↗

bioRxiv2025

Immunomodulatory nanoparticles elicit antifibrotic monocyte activation to resolve murine pulmonary fibrosis

Organ fibrosis presents a substantial disease burden with few therapeutic options. Innate immunity mediates fibrinogenesis, but also plays a major role in fibrinolysis. Here, we show that immunomodulatory nanoparticles (NPs) can harness this endogenous antifibrotic capacity by catalyzing monocyte activation leading to resolution of bleomycin-induced pulmonary fibrosis in vivo. Cargo-free NPs comprised of the degradable biopolymer poly(lactide-co-glycolide) (PLG) induce a transcriptional shift toward antifibrotic immune activation in profibrotic M2 macrophages (M{Phi}s) in vitro. NPs stimulate M2 M{Phi}s toward a glycolytic, rather than fatty acid oxidative, metabolism; suppress canonical M2 markers like arginase-1 (Arg1) and periostin (Postn); and upregulate collagenases, hyaluronidases and immunoregulatory factors. When delivered intravenously in vivo, NPs reverse established bleomycin-induced pulmonary fibrosis and invert the trajectory of over 1,000 genes from pre- to post-treatment according to bulk RNA-sequencing. NPs also suppress profibrotic signaling and increase expression of repair-associated pathways like peroxisome proliferator-activated receptor gamma (PPAR-{gamma}), nuclear retinoic acid receptor (RAR), vascular endothelial growth factor (VEGF), and sphingolipid signaling in fibrotic lungs. Flow cytometry confirms that NPs induce monocyte recruitment to fibrotic lungs via enhanced integrin expression. Altogether, NPs induce a robust pro-regenerative signature comprised of ECM degradation, inflammation resolution, and tissue repair pathways, concomitant with increased NP+ monocyte recruitment to fibrotic lungs. This work demonstrates that monocytes are not intrinsically profibrotic, but rather, their effects are context-dependent, and they retain a capacity for fibrotic resolution under conditions that can be induced by materials with translational potential. Significance StatementOrgan fibrosis can follow from tissue injury and substantially impairs organ function, but it is incurable and has limited therapeutic options. Myeloid immune cells drive fibrosis onset and progression, but they can also mediate fibrosis resolution. We used polymeric NPs made from clinically translatable biomaterials to harness the antifibrotic capacity of immune cells as a fibrosis therapy. We found that intravenous NPs can reprogram myeloid cells to acquire an antifibrotic phenotype in a mouse model of pulmonary fibrosis. NPs increased myeloid activation and pulmonary recruitment while decreasing fibrosis, showing that directed immune activation, instead of suppression, could be an effective therapeutic strategy for fibrosis.

bioengineering↗

bioRxiv2024

Ataxia Telangiectasia patient-derived neuronal and brain organoid models reveal mitochondrial dysfunction and oxidative stress

Ataxia Telangiectasia (AT) is a rare genetic disorder caused by mutations in the ATM gene and is characterized by oxidative stress, premature ageing, and progressive neurodegeneration of the cerebellum. The molecular mechanisms driving the neurological defects AT remain unclear, mainly due to lack of human neuronal models. Here, we use AT patient-derived pluripotent stem cells (iPSCs) and iPSC-derived neurons and brain organoids to comprehensively explore mitochondrial dysfunction, oxidative stress, and senescence phenotypes. We identified mislocalisation of mitochondria, a prevailing reduction in mitochondrial membrane potential, and increased oxidative stress in AT patient-derived iPSC and neuronal cultures that was restored by ATM gene correction. Cortical brain organoids from AT patients also display extensive oxidative stress, increased levels of senescence, and impaired neuronal function that could be counteracted with antioxidant treatment. Transcriptomic analysis identified disruptions in regulatory networks related to mitochondrial function and maintenance, including alterations in the PARP/SIRT signalling axis and dysregulation of key mitophagy and mitochondrial fission-fusion processes. Our study reveals that progressive mitochondrial dysfunction and aberrant ROS production are hallmarks of AT, and lead us to conclude that ATM is a master regulator of mitochondrial homeostasis.

cell biology↗

bioRxiv2020

CXCR4 signaling is counteracted by the naturally occurring CXCR4 antagonist EPI-X 4 in Waldenstrom Macroglobulinemia

CXCR4 expression and downstream signaling have been identified as key factors in malignant hematopoiesis. Thus, up to 40% of all patients with Waldenstroms Macroglobulinemia (WM) carry an activating mutation of CXCR4 that leads to a more aggressive clinical course and inferior outcome upon treatment with the Brutons tyrosine kinase inhibitor ibrutinib. Nevertheless, little is known about physiological mechanisms counteracting CXCR4 signaling in hematopoietic neoplasms. Recently, the endogenous human peptide EPI-X4 was identified as a natural CXCR4 antagonist that effectively blocks CXCL12-mediated receptor internalization and suppresses the migration and invasion of cancer cells towards a CXCL12 gradient. Here, we demonstrate that EPI-X4 efficiently impairs growth of WM cells in vitro and in vivo and blocks their migration towards CXCL12. The CXCR4 inhibitory activity of EPI-X4 is accompanied by decreased expression of genes involved in MAPK signaling and energy metabolism. Notably, the anti-WM activity of EPI-X4 could be further augmented by the rational design of EPI-X4 derivatives showing higher binding affinity to CXCR4. In summary, these data demonstrate that a naturally occurring anti-CXCR4 peptide is able to interfere with WM growth, and that optimized derivatives of EPI-X4 may represent a promising approach in suppressing growth promoting CXCR4 signaling in WM.

cancer biology↗