Physiological aging and inflammation-induced cellular senescence may contribute to oligodendroglial dysfunction in MS

Neurology Medical Laboratory Science Medicine Cell Biology Life Sciences Immunology
physiological aging cellular senescence oligodendrocytes multiple sclerosis white matter

Background Introduction

In this paper, the researchers discuss the impact of aging on the functionality of all cell types in the central nervous system (CNS) and its role in neurological diseases such as multiple sclerosis (MS). However, the molecular mechanisms underlying these age-related changes and their contribution to diseases remain poorly understood. The authors specifically focus on white matter, where subtle anomalies in myelin and axonal nodes in the aging brain and diseases like MS suggest that oligodendrocytes responsible for maintaining myelin structure lose their ability to maintain proper myelin structure and potential functionality with aging and certain diseases. By direct conversion of oligodendrocytes (dchiol) from human donor age groups, the study analyzes age-related changes.

Sources and Authors

This article was co-authored by Farina Windener and several other authors from institutions including the Institute of Neuropathology at Münster University Hospital in Germany, the Montreal Neurological Institute and Department of Neurology and Neurosurgery in Canada, and the Karolinska Institute and Karolinska University Hospital in Sweden. The article was published on April 15, 2024, in the journal “Acta Neuropathologica” and explores the role of oligodendrocyte dysfunction caused by physiological aging and inflammation-induced cellular aging in multiple sclerosis.

Research Process

The paper describes the entire research process in detail, including several specific steps and the use of directly converted oligodendrocytes (dchiol) from human donors of different age groups in experiments. The main steps of the research are as follows:

Cell Isolation and Culture

  • Animal and Human Tissue Samples: The study used tissue samples from mice and humans. Human samples included frontal cortex and subcortical white matter samples from 15 individuals, and fibroblasts obtained from 18 individuals. Additionally, primary oligodendrocyte precursor cells (OPCs) were isolated from mice for the experiments.

Experimental Analysis

  • Transgenic Methods: Human fibroblasts were transgenically converted using Sox10, Olig2, and Nkx6.2 coding regions and selected through puromycin. Cells were divided into three groups: young (fetal to 5 months), adults (22-32 years), and elderly (65-71 years). Results showed that in all age groups, 25-35% of cells expressed O4, but the proportion of MBP+ mature oligodendrocytes significantly declined with donor age.
  • Transcriptome and Methylome Analysis: Comparisons of transcriptomes and methylomes between adult and elderly donors revealed a decline in oligodendrocyte mitochondrial function along with an increase in cellular aging markers. Transcriptome analysis found 1324 differentially expressed genes, with these genes showing significant overlap between the donor’s converted cells and previously published data.

Data Analysis

  • Antibody Staining and FACS Sorting: Various cells were sorted using FACS and immunocytochemistry (ICC) staining was performed to check the developmental and functional states of the cells, with additional metabolic tests such as ROS and ATP detection carried out.
  • RNA Sequencing and Quantitative PCR (qPCR): The transcriptome of dchiol was analyzed using RNA sequencing, and further validation of cellular aging markers was conducted using qPCR.

Main Results

Characteristics of dchiol in Different Age Groups

The study found that: - Elderly dchiol demonstrated significant aging phenotypes, including upregulation of cellular aging markers such as CDKN1A and CDKN2A, increased ROS, and a decline in the proportion of H3K9me3 positive cells. - Despite variations in mtDNA expression, elderly dchiol exhibited higher maximal respiration and reserve capacity compared to other age groups, indicating no significant mitochondrial functional impairment. - Inflammatory environments, such as those associated with inflammatory cytokines, tend to exacerbate the expression of these aging markers.

Conclusion and Application Value

The study indicates that physiological aging and inflammation-induced cellular aging collectively promote oligodendrocyte pathology in inflammatory demyelinating diseases such as multiple sclerosis. This provides a new perspective for understanding the pathological mechanisms of oligodendrocytes in multiple sclerosis. - Scientific Value: Offers detailed molecular mechanisms of oligodendrocytes during the aging process, providing important benchmarks for future research directions. - Application Value: Suggests that targeting these aging-related molecular mechanisms through drugs or other methods may help slow the progression of diseases such as multiple sclerosis.

Research Highlights

  • The study identified aging characteristics of oligodendrocytes and their relationship with inflammation, marking a rare outcome using human cell models.
  • dchiol showed aging-like markers under inflammatory conditions, providing potential targets for future multiple sclerosis treatment.

Other Valuable Information

The findings of this study also indicate that the method of directly converting human fibroblasts into oligodendrocytes is an effective tool for researching other age-related diseases, such as neurodegenerative diseases.

Through these discoveries, the paper provides new insights into understanding and addressing oligodendrocyte pathology in multiple sclerosis, while also demonstrating the potential applications of advanced experimental techniques in medicine and biology.