Biology subjects

McColl, B.

Publications and source records attributed to McColl, B..

3 recordsLinked to original sources

bioRxiv2025

The synovial lining macrophage layer develops in the first weeks of life in a CSF1- and TGFβ- dependent but monocyte-independent process.

Synovial joints harbor a protective lining layer, consisting of fibroblasts and macrophages, which form an epithelial-like barrier. In inflamed joints, lining macrophages regulate both early inflammatory cell influx and resolution. Despite these critical functions, it is currently unknown at what stage during development the synovial macrophage lining is established, and which signals drive this process. Here, we use a combination of genetic models and in vivo perturbations, single cell transcriptomics and imaging to delineate the process of lining formation in mice. We find that the synovial lining is immature at birth and becomes established within the first 3 weeks of life. In this window, the lining is gradually populated with macrophages that originate from fetal sources, proliferate and acquire the lining-specific transcriptional identity. In contrast, monocytes contribute only minimally to the developing lining, and their input remains limited in healthy adulthood. We identify CSF1 and TGF{beta} as key signals in this process, which also involves mechanosensing through PIEZO1. Our study thus identifies the early postnatal window as a critical period for lining macrophage development, with potential lifelong impact on joint health and disease.

immunology↗

bioRxiv2021

Random forest modelling of neuropathological features identifies microglial activation as an accurate pathological classifier of C9orf72-related amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are regarded as two ends of a pathogenetic spectrum, termed ALS-frontotemporal spectrum disorder (ALS-FTSD). However, it is currently difficult to predict where on the spectrum an individual will lie, especially for patients with C9orf72 hexanucleotide repeat expansions (HRE), a mutation associated with both ALS and FTD. It has been shown that both inflammation and protein misfolding influence aspects of ALS and ALS-FTSD disease pathogenesis, such as the manifestation or severity of motor or cognitive symptoms. Previous studies have highlighted markers which may influence C9orf72-associated disease presentation in a targeted fashion, though there has yet to be a systematic and quantitative assessment of common immunohistochemical markers to investigate the significance of these pathways in an unbiased manner. Here we report the first extensive digital pathological assessment with random forest modelling of pathological markers often used in neuropathology practice. This study profiles glial activation and protein misfolding in a cohort of deeply clinically profiled post-mortem tissue from patients with a C9orf72 HRE, who either met the criteria for a diagnosis of ALS or ALS-FTSD. We show that microglial immunohistochemical staining features, both morphological and spatial, are the best independent classifiers of disease status and that clinicopathological associations exist between microglial activation status and cognitive dysfunction in ALS-FTSD patients with C9orf72 HRE. Furthermore, we show that spatially resolved changes in FUS staining are also an accurate predictor of disease status, implying that liquid-liquid phase shift of this aggregation-prone RNA-binding protein may be important in ALS caused by a C9orf72 HRE. Our findings provide further support to the hypothesis of dysfunctional immune regulation and proteostasis in the pathogenesis of C9orf72 ALS and provide a framework for digital analysis of commonly used neuropathological stains as a tool to enrich our understanding of clinicopathological associations between cohorts.

neuroscience↗

bioRxiv2018

A core transcriptional signature of human microglia: derivation and utility in describing region-dependent alterations associated with Alzheimer’s disease

Growing recognition of the pivotal role microglia play in neurodegenerative and neuroinflammatory disorders has accentuated the need to better characterize their function in health and disease. Studies in mouse, have applied transcriptome-wide profiling of microglia to reveal key features of microglial ontogeny, functional profile and phenotypic diversity. Whilst similar in many ways, human microglia exhibit clear differences to their mouse counterparts, underlining the need to develop a better understanding of the human microglial profile. On examining published microglia gene signatures, little consistency was observed between studies. Hence, we set out to define a conserved microglia signature of the human central nervous system (CNS), through a comprehensive meta-analysis of existing transcriptomic resources. Nine datasets derived from cells and tissue, isolated from different regions of the CNS across numerous donors, were subjected independently to an unbiased correlation network analysis. From each dataset, a list of coexpressing genes corresponding to microglia was identified. Comparison of individual microglia clusters showed 249 genes highly conserved between them. This core gene signature included all known markers and improves upon published microglial signatures. The utility of this signature was demonstrated by its use in detecting qualitative and quantitative region-specific alterations in aging and Alzheimers disease. These analyses highlighted the reactive response of microglia in vulnerable brain regions such as the entorhinal cortex and hippocampus, additionally implicating pathways associated with disease progression. We believe this resource and the analyses described here, will support further investigations in the contribution of human microglia towards the CNS in health and disease.\n\nTable of ContentsMain points O_LIPublished microglial transcriptional signatures in mouse and human show poor consensus.\nC_LIO_LIA core transcriptional signature of human microglia with 249 genes was derived and found conserved across brain regions, encompassing the CNS.\nC_LIO_LIThe signature revealed region-dependent microglial alterations in Alzheimers, highlighting susceptible CNS regions and the involvement of TYROBP signaling.\nC_LI

neuroscience↗