Biology subjects

Lloyd, A. C.

Publications and source records attributed to Lloyd, A. C..

4 recordsLinked to original sources

bioRxiv2026

Quantitative spatial connectomics of liver reveals a partially exposed sympathetic network that integrates multiple cell types across the portal tract

Peripheral tissues are innervated by sparse axonal networks that regulate homeostasis, regeneration and disease, yet their three-dimensional architecture and cellular targets remain largely unknown. Here, we present an EM workflow for quantitative 3D spatial connectomics to define these networks. We identify the mouse liver connectome as a meshwork, rather than a tree-like structure, of mainly sympathetic axons, in which partial Schwann cell coverage is associated with exposed varicosities along the length of individual axons with large regions of the network devoid of glial coverage. Axon tracing identified axonal terminals throughout the network, but the vast majority of cellular contacts involved exposed 'en passant' varicosities. While both terminals and varicosities innervated the vasculature, most synaptic-like contacts involved hepatocytes, fibroblasts, macrophages, and the stem-cell niche, with all individual axons contacting different cell types along their length, highlighting the network nature of liver innervation, the potential for co-ordinating tissue function and demonstrating the power of this approach for decoding connectivity in peripheral tissues.

neuroscience↗

bioRxiv2025

Microenvironmental TGF-β is an early driver of NF1-associated tumour formation

Neurofibromatosis Type 1 (NF1) is a common tumour predisposition syndrome characterised by neurofibromas - Nf1-/- Schwann cell (SC)-derived tumours of peripheral nerves. We and others have shown that Nf1 loss in SCs is insufficient for neurofibroma formation but cooperates with an injury microenvironment to form tumours, but the mechanisms remained unknown. Here, we identify macrophage-secreted TGF-{beta} as the microenvironmental injury signal that is essential for tumourigenesis. Analysis of the earliest stages of neurofibroma formation showed that tumours arise from a population of Nf1-/- SCs that escape the regenerating nerve shortly after injury. Here, they reside in a distinct microenvironment conducive for tumourigenesis, where TGF-{beta} disrupts SC/axonal interactions and SC re-differentiation. Pharmacological inhibition of TGF-{beta} for a short therapeutic window during this early stage inhibited tumour formation, highlighting the potential to normalise Nf1-/- SCs and identifying TGF-{beta} as a potential therapeutic target to both treat and prevent neurofibroma formation.

cell biology↗

bioRxiv2019

N-cadherin-Presented Slit Repulsive-Cues Direct Collective Schwann cell Migration

Collective cell migration is fundamental for the development of organisms and in the adult, for tissue regeneration and in pathological conditions such as cancer. Migration as a coherent group requires the maintenance of cell-cell interactions, while contact-inhibition-of-locomotion (CIL), a local repulsive force, propels the group forward. Here we show that the cell-cell interaction molecule, N-cadherin, regulates both adhesion and repulsion processes during Schwann cell collective migration, which is required for peripheral nerve regeneration. However, distinct from its role in cell-cell adhesion, the repulsion process is independent of N-cadherin trans-homodimerisation and the associated adherens junction complex. Rather, the extracellular domain of N-cadherin acts to traffic a repulsive Slit2/Slit3 signal to the cell-surface. Inhibiting Slit2/Slit3 signalling inhibits CIL and subsequently collective SC migration, resulting in adherent, non-migratory cell clusters. These findings provide insight into how opposing signals can mediate collective cell migration and how CIL pathways are promising targets for inhibiting pathological cell migration.

molecular biology↗

bioRxiv2019

Macrophages enforce the blood nerve barrier

The specialised blood barriers of the nervous system are important for protecting the neural environment but can hinder therapeutic accessibility1,2. Studies in the central nervous system (CNS) have shown the importance of the cellular components of the neuro-vascular unit for blood-brain barrier (BBB) function. Whilst the endothelial cells (ECs) confer barrier function with specialised tight junctions (TJs) and low levels of transcytosis, pericytes and astrocytes provide complete coverage of the ECs and both deliver essential signals for the development and maintenance of the BBB3-9. In contrast, the blood-nerve barrier (BNB) of the peripheral nervous system (PNS) remains poorly defined10. Here, we show that the vascular unit in the PNS has a distinct cellular composition with only partial coverage of the BNB-forming ECs. Using a mouse model, in which barrier function can be controlled11, we show the BNB, while less tight than the BBB, is maintained by low levels of transcytosis and the TJs of the ECs, with opening of the barrier associated with increased transcytosis. Importantly, we find that while ECs of the PNS have higher transcytosis rates than those of the CNS, the barrier is reinforced by resident macrophages that specifically engulf leaked material. This identifies a distinct role for macrophages as an important component of the BNB acting to protect the PNS environment with implications for improving therapeutic delivery to this tissue.

neuroscience↗