Do the Changes of the Mechanical Environment in MS Lesions Affect Myelin Repair and Responses of Oligodendrocytes to Pro-Myelinating Drugs?
Abstract
This project addresses the FY19 MSRP focus area "Promoting central nervous system regenerative potential in demyelinating conditions; understanding potential causes for impaired repair, including extrinsic and cell intrinsic factors." Myelin repair in MS patients is a key regenerative process that can protect neurons from dying and prevent permanent neurological disabilities. For reasons that are not well understood, this process in MS patients is not efficient enough to stop progression of neurodegeneration. Therefore, therapies that stimulate remyelination are actively sought. Despite efforts to develop remyelination therapies, there is currently no approved therapy that can stimulate myelin repair in MS. One of the roadblocks in developing effective remyelination therapies is incomplete understanding of key factors in the tissue environment of MS lesions that inhibit myelin repair. To address this gap, we will examine for the first time how myelination and remyelination depend on key biophysical factors that were previously not possible to consider systematically. These factors include intrinsic stiffness, diameter, and density of the neuronal axons that are ensheathed with myelin by other (glial or "glue") cells in brain tissue. These features change significantly in the tissue as disease progresses, and it is likely that this serves as extrinsic cues that inhibit the capacity of glial cells to repair myelin. Measuring remyelination in controlled biophysical environments was thus far not possible due to the lack of appropriate experimental tools. To enable these critical measurements, we have developed a novel platform to study myelination, called Artificial Axons. In this platform we use biocompatible polymer materials to mimic biological axons. This not only allows us to directly observe and quantify myelination much easier than in traditional assays, but also to vary biophysical parameters in a controlled way, such that they reproduce conditions existing in MS lesions and a healthy tissue. Therefore, Artificial Axons provide a more biologically relevant assay to study remyelination and screening for pro-myelinating drug candidates in disease-like conditions. In contrast, conventional research tools for drug screening (e.g., tissue culture polystyrene dishes) are flat and so do not allow viewing of the three-dimensional wrapping process of myelination, and are many orders of magnitude stiffer than nervous tissue and neurons. This disparity may contribute to incomplete or misleading conclusions about the effects of screened drugs on remyelination in patients. Here, we propose to test the hypothesis that the effects of pro-myelinating compounds will differ between the MS lesion biophysical environment reproduced in Artificial Axons platform and the traditional tissue culture plastic-based assays. By understanding how physical cues in MS lesions affect myelin repair, including the stiffness of the neuronal axons, we can potentially discover new possibilities for remyelination therapies. Moreover, the results of this research may lead to a shift from traditional drug screening approaches toward biomimetic assays that more credibly represent the biophysical environment of MS lesions that discourage remyelination. Our Artificial Axons platform provides such a biomimetic, tunable, and reductionist tool that is suitable both for basic research of disease mechanisms as well as a predictive high throughput drug screening in pharmaceutical industry setup. We expect that this platform will significantly reduce time and cost of drug development by more accurately identifying compounds in the pipeline that will promote actual remyelination in vivo. The results of this project are an enabling step in finding treatments that promote remyelination for demyelinating conditions including MS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010365
Entities
People
- Krystyn Van Vliet
Organizations
- Massachusetts Institute of Technology
- United States Army