Biology subjects

Lin, J.-P.

Publications and source records attributed to Lin, J.-P..

4 recordsLinked to original sources

bioRxiv2023

A 4D transcriptomic map for the evolution of multiple sclerosis-like lesions in the marmoset brain

Single-time-point histopathological studies on postmortem multiple sclerosis (MS) tissue fail to capture lesion evolution dynamics, posing challenges for therapy development targeting development and repair of focal inflammatory demyelination. To close this gap, we studied experimental autoimmune encephalitis (EAE) in the common marmoset, the most faithful animal model of these processes. Using MRI-informed RNA profiling, we analyzed [~]600,000 single-nucleus and [~]55,000 spatial transcriptomes, comparing them against EAE inoculation status, longitudinal radiological signals, and histopathological features. We categorized 5 groups of microenvironments pertinent to neural function, immune and glial responses, tissue destruction and repair, and regulatory network at brain borders. Exploring perilesional microenvironment diversity, we uncovered central roles of EAE-associated astrocytes, oligodendrocyte precursor cells, and ependyma in lesion formation and resolution. We pinpointed imaging and molecular features capturing the pathological trajectory of WM, offering potential for assessing treatment outcomes using marmoset as a platform. One sentence summaryA cross-modality study to identify the spatiotemporal-based diversity of primate brain cells during white matter inflammatory demyelination to inform lesion detection, stratification, and management in multiple sclerosis.

neuroscience↗

bioRxiv2023

Lipofuscin-like autofluorescence within microglia and its impact on studying microglial engulfment

Engulfment of cellular material and proteins is a key function for microglia, a resident macrophage of the central nervous system (CNS). Among the techniques used to measure microglial engulfment, confocal light microscopy has been used the most extensively. Here, we show that autofluorescence (AF), likely due to lipofuscin and typically associated with aging, can also be detected within microglial lysosomes in the young mouse brain by light microscopy. This lipofuscin-AF signal accumulates first within microglia and increases with age, but it is not exacerbated by amyloid beta-related neurodegeneration. We further show that this lipofuscin-AF signal within microglia can confound the interpretation of antibody-labeled synaptic material within microglia in young adult mice. Finally, we implement a robust strategy to quench AF in mouse, marmoset, and human brain tissue.

neuroscience↗

bioRxiv2021

Microenvironment Impacts the Molecular Architecture and Interactivity of Resident Cells in Marmoset Brain

The microenvironments of the brain consist of specialized cell types that together influence physiological functions in health and pathological outcomes in disease. Despite apparent differences in the density of neurons and oligodendrocytes in various milieus, such as gray matter (GM) and white matter (WM), the extent of structural and functional heterogeneity of other resident cells remains unclear. We profiled RNA in ~500,000 nuclei from 19 tissue types across the central nervous system of the healthy adult common marmoset (Callithrix jacchus) and mapped 87 identified subclusters (including neurons, glia, and vasculature) spatially onto a 3D MRI atlas. We performed cross-species comparison, explored regulatory pathways, surveyed cellular determinants of neurological disorders, and modeled regional intercellular communication. We found spatially segregated microglia, oligodendrocyte lineage cells, and astrocytes in WM and GM. WM-glia are diverse, are enriched with genes involved in stimulus response and biomolecule modification, and interact with other resident cells more extensively than their GM counterparts. GM-glia preserve the expression of developmental morphogens into adulthood and share 6 differentially enriched transcription factors that restrict the transcriptome complexity. Our work in marmoset, an experimentally tractable animal model with >5 times more WM volume and complexity than mouse, identifies novel WM-glia subtypes and their contributions to different neurological disorders. A companion Callithrix jacchus Primate Cell Atlas (CjPCA) is available through an online portal https://cjpca.ninds.nih.gov to facilitate data exploration.

neuroscience↗

bioRxiv2017

LRP1 Regulates Peroxisome Biogenesis and Cholesterol Homeostasis in Oligodendrocytes and is Required in CNS Myelin Development and Repair

The low-density lipoprotein related-receptor-1 (LRP1) is a large endocytic and signaling receptor. We show that Lrp1 is required for proper CNS myelinogensis in vivo. Either global inducible or oligodendrocyte (OL)-lineage specific ablation of Lrp1 impairs myelin development and adult white matter repair. In primary oligodendrocyte progenitor cells (OPCs), Lrp1 deficiency reduces cholesterol levels and attenuates differentiation into mature OLs. Despite a strong increase in the sterol-regulatory element-binding protein-2, Lrp1-/- OPCs are not able to maintain normal cholesterol levels, suggesting more global metabolic deficits. Mechanistic studies identified a decrease in peroxisomal biogenesis factor-2 and a reduction in peroxisomes localized to OL processes. Treatment of Lrp1-/- OPCs with cholesterol or pharmacological activation of peroxisome proliferator-activated receptor-{gamma} with pioglitazone is not sufficient to promote differentiation; however when combined, cholesterol and pioglitazone treatment enhance OL production. Collectively, our studies identify a novel link between LRP1, peroxisomes, and OPC differentiation during white matter development and repair.

neuroscience↗