Biology subjects

Atkinson, P. J.

Publications and source records attributed to Atkinson, P. J..

5 recordsLinked to original sources

bioRxiv2025

Durable reconstitution of sinonasal epithelium by transplant of CFTR gene corrected airway stem cells

Modulator agents that restore cystic fibrosis transmembrane conductance regulator (CFTR) function have revolutionized outcomes in cystic fibrosis, an incurable multisystem disease. Barriers exist to modulator use, making local CFTR gene and cell therapies attractive, especially in the respiratory tract. We used CRISPR to gene-correct CFTR in upper airway basal stem cells (UABCs) and show durable local engraftment into recipient murine respiratory epithelium. Interestingly, the human cells recapitulate the in vivo organization and differentiation of human sinus epithelium, with little expansion or contraction of the engrafted population over time, while retaining expression of the CFTR transgene. Our results indicate that human airway stem cell transplantation with locoregional restoration of CFTR function is a feasible approach for treating CF and potentially other diseases of the respiratory tract.

bioengineering↗

bioRxiv2024

Single-cell, spatial, and fate-mapping analyses uncover niche dependent diversity of cochlear myeloid cells.

Recent advances in fate mapping and single-cell technologies have revealed how the dynamics and function of tissue-resident macrophages are shaped by their environment. However, macrophages in sensory organs such as the cochlea where the central nervous system and peripheral nervous system meet remain understudied. Combining single-cell transcriptomics, fate mapping, and parabiosis experiments, we show that five types of myeloid cells including three tissue-resident macrophage subpopulations, coexist in the mouse cochlea. The three macrophage subsets showed different potential functions in relationship with their specific topography across cochlear compartments. Further analysis revealed that they were partially derived from yolk sac progenitors during development, while in adulthood, most cochlear macrophages were long-term resident. Finally, we showed that cochlear macrophage morphology and density changed during aging. Our findings show that cochlea is a microenvironment with a unique heterogeneity of macrophages in terms of gene expression, spatial distribution, ontogeny, and function.

immunology↗

bioRxiv2022

Single-cell transcriptomic atlas reveals increased regeneration in diseased human inner ears

Mammalian inner ear hair cell loss leads to permanent hearing and balance dysfunction. In contrast to the cochlea, vestibular hair cells of the murine utricle have some regenerative capacity. Whether human utricular hair cells regenerate remains unknown. Here we procured live, mature utricles from organ donors and vestibular schwannoma patients, and present a validated single-cell transcriptomic atlas at unprecedented resolution. We describe previously unknown markers of 25 sensory and non-sensory cell types, with genes of hair cell and supporting cell subtypes displaying striking divergence between mice and humans. We further uncovered transcriptomes unique to hair cell precursors, which we validated to be 14-fold more robust in vestibular schwannoma utricles, representing ongoing regeneration in humans. Lastly, trajectory analysis of the supporting cell-hair cell axis revealed 5 distinct patterns of dynamic gene expression and associated pathways, including mTOR signaling and synaptogenesis. Our dataset constitutes a foundational resource, accessible via a web-based interface, serving to advance knowledge of the normal and diseased human inner ears and tools to stimulate human inner ear regeneration.

cell biology↗

bioRxiv2021

Selection and structural characterisation of anti-TREM2 scFvs that reduce levels of shed ectodomain

Single point mutations in TREM2, a receptor expressed by microglia in the brain, are associated with an increased risk of neurodegeneration including Alzheimers disease. Numerous studies support a role for TREM2 in sensing damaging stimuli and triggering signalling cascades necessary for neuroprotection. Despite its significant role, ligands and regulators of TREM2 activation, and the mechanisms governing TREM2-dependent responses and its cleavage from the membrane, remain poorly characterised. Here, we present phage display generated scFv antibody binders to human TREM2 ectodomain. Cocrystal structures revealed the binding of two scFvs to an epitope on the globular TREM2 domain distal to the putative ligand-binding site. Enhanced functional activity was observed for oligomeric scFv species which inhibited the production of soluble TREM2 in a HEK293 cell model. We hope that detailed characterisation of their epitopes and properties will facilitate the use of these renewable binders as structural and functional biology tools for TREM2 research.

molecular biology↗

bioRxiv2020

Inhibition of IL34 unveils tissue-selectivity and is sufficient to reduce microglial proliferation in chronic neurodegeneration

The proliferation and activation of microglia, the resident macrophages in the brain, is a hallmark of many neurodegenerative diseases such as Alzheimers disease (AD) and prion disease. Colony stimulating factor 1 receptor (CSF1R) is critically involved in regulating microglial proliferation, and CSF1R blocking strategies have been recently used to modulate microglia in neurodegenerative diseases. However, CSF1R is broadly expressed by many cellular types and the impact of its inhibition on the innate immune system is still unclear. CSF1R can be activated by two independent ligands, CSF1 and interleukin 34 (IL-34). Recently, it has been reported that microglia development and maintenance depend on IL-34 signalling. In this study, we evaluate the inhibition of IL-34 as a novel strategy to reduce microglial proliferation in neurodegenerative diseases, using the ME7 model of prion disease. Selective inhibition of IL-34 showed no effects on peripheral macrophages populations in healthy mice, avoiding the side effects observed after CSF1R inhibition on the systemic compartment. However, we observed a reduction in microglial proliferation after IL-34 inhibition in prion-diseased mice, indicating that microglia could be more specifically targeted by reducing IL-34 and that this ligand plays an important role in the modulation of microglia population during neurodegeneration. Overall, our results suggest that control of microglial response through IL-34 blockade could be a potential therapeutic approach in neurodegenerative diseases.

neuroscience↗