A5020821513- Neurogenesis and neuroplasticity mechanisms
- Nerve injury and regeneration
- Amyotrophic Lateral Sclerosis Research
- Neuroinflammation and Neurodegeneration Mechanisms
- Neuropeptides and Animal Physiology
- Pluripotent Stem Cells Research
- Neurogenetic and Muscular Disorders Research
- Axon Guidance and Neuronal Signaling
- Spinal Cord Injury Research
- Neuroendocrine regulation and behavior
- 3D Printing in Biomedical Research
- Olfactory and Sensory Function Studies
- RNA Interference and Gene Delivery
- Hypothalamic control of reproductive hormones
- Veterinary Orthopedics and Neurology
- Neural dynamics and brain function
- Stress Responses and Cortisol
- Mitochondrial Function and Pathology
- Alzheimer's disease research and treatments
- Prion Diseases and Protein Misfolding
- Neuroscience and Neural Engineering
- Insect symbiosis and bacterial influences
- Nerve Injury and Rehabilitation
- Genetic Neurodegenerative Diseases
- Mosquito-borne diseases and control
University of Cambridge
2006-2025
Cambridge University Hospitals NHS Foundation Trust
2022-2024
Wellcome/MRC Cambridge Stem Cell Institute
2021-2024
Addenbrooke's Hospital
2017-2024
Stem Cell Institute
2018
Wellcome Trust
2018
Semmelweis University
1996-2006
University of Glasgow
2000-2001
Abstract Amyotrophic lateral sclerosis overlapping with frontotemporal dementia (ALS/FTD) is a fatal and currently untreatable disease characterized by rapid cognitive decline paralysis. Elucidating initial cellular pathologies central to therapeutic target development, but obtaining samples from presymptomatic patients not feasible. Here, we report the development of cerebral organoid slice model derived human induced pluripotent stem cells (iPSCs) that recapitulates mature cortical...
Transplanted olfactory ensheathing cells (OECs) are able to remyelinate demyelinated axons and support regrowth of transected after transplantation into the adult CNS. Schwann (SCs) share these repair properties but have limitations imposed on their behavior by presence astrocytes (ACs). Because OECs exist alongside in bulb, we hypothesized that they advantages over SCs transplant-mediated CNS due an increased ability integrate migrate within astrocytic environment. In this study, tested...
Motor neurons (MNs) and astrocytes (ACs) are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), but their interaction sequence molecular events leading to MN death remain unresolved. Here, we optimized directed differentiation induced pluripotent stem cells (iPSCs) into highly enriched (> 85%) functional populations spinal cord MNs ACs. We identify significantly increased cytoplasmic TDP-43 ER stress as primary pathogenic patient-specific valosin-containing protein...
Abstract The role of remote astrocyte (AC) reaction to central or peripheral axonal insult is not clearly understood. Here we use a transgenic approach compare the direct influence normal with diminished AC reactivity on neuronal integrity and synapse recovery following extracranial facial nerve transection in mice. Our model allows straightforward interpretations AC–neuron signalling by reducing confounding effects imposed inflammatory cells. We show evidence that perineuronal reactive ACs...
Diversified neurons are essential for sensorimotor function, but whether astrocytes become specialized to optimize circuit performance remains unclear. Large fast α-motor (FαMNs) of spinal cord innervate fast-twitch muscles that generate peak strength. We report ventral horn express the inward-rectifying K+ channel Kir4.1 (a.k.a. Kcnj10) around MNs in a VGLUT1-dependent manner. Loss astrocyte-encoded selectively altered FαMN size and function led reduced Overexpression was sufficient...
Abstract Astrocyte responses to neuronal injury may be beneficial or detrimental recovery, but the mechanisms that determine these different are poorly understood. Here we show ephrin type-B receptor 1 (EphB1) is upregulated in injured motor neurons, which turn can activate astrocytes through ephrin-B1-mediated stimulation of signal transducer and activator transcription-3 (STAT3). Transcriptional analysis shows EphB1 induces a protective anti-inflammatory signature astrocytes, partially...
Schwann cell (SC) and olfactory ensheathing (OEC) transplantation has been shown experimentally to promote CNS axonal regeneration remyelination. To advance this technique into a clinical setting it is important be able follow the fates of transplanted cells by noninvasive imaging. Previous studies, using complex modification processes enable uptake contrast agents, have that labeled in vitro with paramagnetic agents rodent can visualized magnetic resonance imaging (MRI). Here we show SCs...
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are primarily genetic in ~20% of patients. Mutations C9ORF72 the most frequent cause, but it is not understood why there notable regional pathology. An increased burden mitochondrial DNA (mtDNA) mutations ALS-FTLD brains implicates mechanisms; however, remains unclear how when these arise. To address this, we generated cerebral organoids derived from human-induced pluripotent stem cells (hiPSCs) patients with...
Mitochondrial diseases frequently affect the brain leading to severe and disabling neurological symptoms. The heteroplasmic m.3243A>G mutation in MT-TL1, encoding mt-tRNALeu, is responsible for ~80% of mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS), which one most characteristic syndromes, disability early death. There are no animal models harbouring this provide precise mechanistic insights informing therapeutic interventions. Here, we generated a human...
Olfactory ensheathing cells (OECs) are candidate for transplant-mediated repair of persistent demyelination in diseases such as multiple sclerosis. If this approach is to make the transition from laboratory clinic, an important issue most suitable composition OEC transplant. Isolation OECs involves concurrent isolation other cell types, and specific selection techniques required produce purified OECs. In study we address whether purity transplant affects their ability remyelinate....
Intraspinal transplantation of olfactory glial cells (OGC) has produced well-defined beneficial effects in experimental rodent models spinal cord injury (SCI) and therefore considerable promise as a treatment for severe SCI human patients. In this study, we used clinical canine cases to determine whether derivation OGC from an autologous source was feasible. From the nerve fiber layer single bulb, were able generate 5 × 106 each patient within 3 weeks. Of population, 72% p75+ OGC, 20%...
Abstract Zika virus (ZIKV), an emerging mosquito-borne flavivirus, is associated with congenital neurological complications. Here, we investigate potential pathological correlates of gene expression in representative ZIKV strains through RNA sequencing and ribosome profiling. In addition to the single long polyprotein found all flaviviruses, identify translation unrecognised upstream open reading frames (uORFs) genomic 5′ region. Asian/American strains, ribosomes translate uORF1 uORF2,...
MotivationMicroelectrode array (MEA) recordings of neuronal activity are an essential functional assay for evaluating in vitro models neurodevelopment and neurological diseases. However, most studies limited to comparing firing burst rates. We have previously shown that 3D human cerebral organoids develop microscale networks. The network-level features, which predict cellular-scale information processing efficiency, can provide a bioinformatic phenotype network function MEA from tissues....
Glial growth factor-2 (GGF-2) is a neuronally derived isoform of neuregulin shown in vitro to promote proliferation and survival oligodendrocytes, the myelinating cells CNS. Enhanced remyelination has been demonstrated vivo following systemic delivery human recombinant GGF-2 (rhGGF-2) experimental autoimmune encephalomyelitis (EAE). However, it uncertain whether this result direct effects rhGGF-2 on oligodendrocyte lineage or due modulation immune inflammatory response. If enhanced was then...
Summary Microelectrode array (MEA) recordings are commonly used to compare firing and burst rates in neuronal cultures. MEA can also reveal microscale functional connectivity, topology, network dynamics—patterns seen brain networks across spatial scales. Network topology is frequently characterized neuroimaging with graph theoretical metrics. However, few computational tools exist for analyzing from recordings. Here, we present a MATLAB analysis pipeline (MEA-NAP) raw voltage time-series...
Abstract Pleckstrin homology-like domain family A—member 3 (PHLDA3) has recently been identified as a player in adaptive and maladaptive cellular stress pathways. The outcome of pleckstrin signalling was shown to vary across different cell types states. It emerges that its expression protein level are highly increased amyotrophic lateral sclerosis (ALS) patient-derived astrocytes. Whether it orchestrates supportive or detrimental function remains unexplored the context neurodegenerative...
Purpose of review This article reviews recent advances in the use cell transplantation to promote recovery from traumatic injury CNS, focusing on axonal regeneration spinal cord. Recent findings The significant reported are: (1) increased expression inhibitory chondroitin sulphate-proteoglycans host tissue following Schwann transplantation, highlighting effects transplant may have ability support regeneration; (2) embryonic and neural stem cells into experimental models cord injury; (3) that...