Biology subjects

Ha, S. M.

Publications and source records attributed to Ha, S. M..

4 recordsLinked to original sources

bioRxiv2023

Olfactory ensheathing cells are hybrid glial cells that promote neural repair

Olfactory ensheathing cells (OECs) are unique glial cells found in both central and peripheral nervous systems where they support continuous axonal outgrowth of olfactory sensory neurons to their targets. Previously we reported that following severe spinal cord injury, OECs transplanted near the injury site modify the inhibitory glial scar and facilitate axon regeneration past the scar border and into the lesion. To better understand the mechanisms underlying the reparative properties of OECs, we used single-cell RNA-sequencing of OECs from adult rats to study their gene expression programs. Our analyses revealed five diverse OEC subtypes, each expressing novel marker genes and pathways indicative of progenitor, axonal regeneration, secreted molecules, or microglia-like functions. We found substantial overlap of OEC genes with those of Schwann cells, but also with microglia, astrocytes, and oligodendrocytes. We confirmed established markers on cultured OECs, and localized select top genes of OEC subtypes in olfactory bulb tissue. We also show that OECs secrete Reelin and Connective tissue growth factor, extracellular matrix molecules which are important for neural repair and axonal outgrowth. Our results support that OECs are a unique hybrid glia, some with progenitor characteristics, and that their gene expression patterns indicate functions related to wound healing, injury repair and axonal regeneration.

neuroscience↗

bioRxiv2023

Ketogenic diet therapy for pediatric epilepsy is associated with alterations in the human gut microbiome that confer seizure resistance in mice

The gut microbiome modulates seizure susceptibility and the anti-seizure effects of the ketogenic diet (KD) in animal models, but whether these relationships translate to KD therapies for human drug-resistant epilepsy is unclear. Herein, we find that the clinical KD shifts the function of the gut microbiome in children with refractory epilepsy. Colonizing mice with KD-associated human gut microbes confers increased resistance to 6-Hz psychomotor seizures, as compared to colonization with gut microbes from matched pre-treatment controls. Parallel analysis of human donor and mouse recipient metagenomic and metabolomic profiles identifies subsets of shared functional features that are seen in response to KD treatment in humans and preserved upon transfer to mice fed a standard diet. These include enriched representation of microbial genes and metabolites related to anaplerosis, fatty acid beta-oxidation, and amino acid metabolism. Mice colonized with KD-associated human gut microbes further exhibit altered hippocampal and frontal cortical transcriptomic profiles relative to colonized pre-treatment controls, including differential expression of genes related to ATP synthesis, glutathione metabolism, oxidative phosphorylation, and translation. Integrative co-occurrence network analysis of the metagenomic, metabolomic, and brain transcriptomic datasets identifies features that are shared between human and mouse networks, and select microbial functional pathways and metabolites that are candidate primary drivers of hippocampal expression signatures related to epilepsy. Together, these findings reveal key microbial functions and biological pathways that are altered by clinical KD therapies for pediatric refractory epilepsy and further linked to microbiome-induced alterations in brain gene expression and seizure protection in mice.

microbiology↗

bioRxiv2022

Cross-tissue multiomics studies reveal gut-brain interactions mediating the effect of Akkermansia muciniphila in counteracting fructose-induced obesity

High fructose diet is a major risk factor for metabolic syndrome (MetS). The gut bacterium Akkermansia muciniphila (A. muciniphila) has been shown to improve fructose-induced MetS, but the underlying mechanism remains unclear. Here, we investigated how A. muciniphila modulates fructose-induced MetS using multitissue, multiomics studies encompassing gut microbiota, plasma and gut metabolome, and hypothalamus single cell RNA-sequencing. A. muciniphila colonization enriched beneficial gut bacteria, increased metabolites including bile acids, endocannabinoids, and vitamins, and activated genes related to oxytocin and vasopressin signaling in hypothalamic neurons. Multiomics network analysis prioritized the metabolite oleoylethanolamide (OEA), an endocannabinoid analogue, as a potential regulator of gut-hypothalamic interaction conferred by A. muciniphila, its associated beneficial bacteria, and bile acid remodeling. Oral administration of OEA to fructose-fed mice recapitulated A. muciniphila effects, including counteracting body weight gain, enhancing thermogenesis, and ameliorating glucose intolerance. Concomitantly, OEA supplementation stimulated expression of its receptors and tight junction genes in the intestine, as well as neuronal activation marker c-Fos and oxytocin and vasopressin signaling genes in the hypothalamus. These findings underscore the regulatory role of A. muciniphila in gut microbiota homeostasis and metabolomic reprogramming, and pinpoint OEA as a key mediator of its action on the gut-hypothalamus axis in alleviating fructose-induced MetS.

systems biology↗

bioRxiv2022

Neurodevelopmental Patterns of Early Postnatal White Matter Maturation Represent Distinct Underlying Microstructure and Histology

During the early postnatal period, cerebral white matter undergoes rapid maturation through a complex series of interrelated cellular and histogenetic processes. Accurately quantifying these processes is important for improving understanding of early brain development, developmental abnormalities related to prematurity, and neurodevelopmental diseases. Past efforts have used magnetic resonance imaging (MRI) to track these developmental processes in vivo. However, most previous studies have relied on single imaging modality data and have often been limited by small samples and analytics that do not evaluate complex multivariate imaging patterns. Here, we applied an advanced unsupervised multivariate pattern analysis technique, non-negative matrix factorization (NMF), to T2w/T1w signal ratio maps from a large cohort of newborns (Developing Human Connectome Project [dHCP], n=342), revealing patterns of synchronous white matter maturation. These patterns showed divergent age-related maturational trajectories and differential susceptibility to premature birth, which were replicated in an independent large sample of newborns (Early Life Adversity, Biological Embedding, and Risk for Developmental Precursors of Mental Disorders [eLABE], n=239). Furthermore, we showed that T2w/T1w signal variations in white matter maturational patterns are explained by differential contributions of white matter microstructure indices (i.e., free water content and neurite density index) derived from neurite orientation dispersion and density imaging (NODDI) modeling of diffusion-weighted MRI. Finally, we demonstrated how white matter maturation patterns relate to distinct histological features by comparing our findings with postmortem late fetal/early postnatal brain tissue staining. Together, these results delineate a novel MRI representation of white matter microstructural and histological reorganization during the early postnatal development.

neuroscience↗