Mechanical Properties of the Injured CNS: Implications for Remyelination and Axonal Repair
Abstract
Despite the presence of oligodendrocyte progenitor cells (OPC) capable of regenerating myelin after its loss, chronic MS lesions in the brain and spinal cord are characterized by incomplete repair; yet, the underlying cause remains unknown. To begin understanding potential mechanisms behind remyelination failure in MS, we hypothesize that the MS lesion environment may alter the mechanical properties of the brain tissue and therefore negatively impact the ability of OPC to make new myelin. Within this context, our lab and others have found that OPC grown in "high-stiffness" conditions are not capable of forming myelin. Furthermore, we have preliminary data indicating that acute and chronic demyelinated lesions (in rodents and humans) have different mechanical properties, with chronic lesions exhibiting increased stiffness and impaired repair. This grant proposal plans to measure the mechanical properties of brain regions with successful myelin formation and compare them with those of regions with impaired or defective myelin repair in mouse and human brain tissue. This primary goal will be achieved using Atomic Force Microscopy (AFM), a technique that allows accurate and detailed measurements of the mechanical properties of CNS tissue at the micrometer scale, from animal models of acute and chronic demyelination as well as from human MS post-mortem tissue. We have implemented the use of this technology to generate preliminary data, which support the model. This experimental aim will allow us to understand what the "optimal mechanical properties for remyelination" are. The second aim will then test whether synthetic materials of different stiffness can be employed for preconditioning human-derived OPC to make myelin. The idea would be that OPC exposed to materials of the "right stiffness" will be capable of remyelinating, even if transplanted in a chronically demyelinated lesion, and thereby promote repair and neuroprotection. By investigating how OPC behavior is affected by changes in tissue stiffness, the work proposed here could help to identify new treatments for myelin repair. The products of this research might also have short- to mid-term impact on ongoing efforts to develop cell-based therapies, involving transplantation of human-derived OPC to promote myelin repair, and also impact the design of biocompatible materials supportive of neuronal and glial development that incorporate optimal mechanical stimulation of these cells. These studies will primarily benefit MS patients with secondary-progressive disease, where therapies aimed at improving remyelination and promoting neuroprotection are urgently needed.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810525
Entities
People
- Carmen Melendez-Vasquez
Organizations
- Hunter College
- United States Army