Overcoming Human-Specific Obstacles to Successful Remyelination in Multiple Sclerosis
Abstract
The Focus Area of this application is Central Nervous System Regenerative Potential in Demyelinating Conditions. The brain contains a population of neural stem/progenitor cells that remain dormant during adulthood. These cells are commonly referred to as oligodendrocyte progenitor cells (OPCs) and give rise to specialized cells known as oligodendrocytes. Oligodendrocytes and the myelin that they produce are vital for normal neurological function. Loss of or damage to oligodendrocytes in demyelinating diseases such as Multiple Sclerosis contributes to severe and progressive disability. Importantly, OPCs can generate new oligodendrocytes, restoring lost myelin and promoting functional regeneration, a process known as remyelination. As such, OPCs represent a promising untapped source of stem/progenitors that when properly stimulated could lead to significant regeneration in MS and other diseases. In mouse and rat models of demyelination, the endogenous process of remyelination is incredibly efficient with remyelination and functional recovery occurring within several weeks of the initial insult. In contrast, human remyelination is thought to occur slowly over several months and is often insufficient. As a result, regions of permanent or chronic demyelination are commonly observed in patients with MS. As chronic demyelination is associated with neuronal death and the loss of neurological function, therapies aimed at enhancing remyelination are expected to restore lost function and prevent disease progression in MS. The primary goal of this project is to identify and overcome the factors that distinguish the failure of myelin repair observed in human MS from the successful repair processes occurring in rodent models. This project will address two specific aspects that distinguish human and mouse lesions: first, specific molecular signaling events in human and mouse, and second, the huge difference in size of the demyelinating injury. Molecular signaling: In preliminary studies, we have established a novel cell culture system by which we can identify the molecules selectively expressed by human OPCs, which limit their own proliferation and may become pathologically disrupted in MS. In so doing, we identified IGFBP2, a secreted protein that can regulate cell-cell signaling. IGFBP2 possesses a uniquely human structure that is capable of inhibiting OPC proliferation in the human but not mouse brain. In this project, we will characterize the role of IGFBP2 and other candidate proteins both in the dish but also following transplantation of human cells into humanized mouse models. This will allow us to establish whether hOPCs regulate their proliferation in a unique manner compared to mice and, importantly, whether human-specific processes are active that may prevent successful remyelination in MS. Size: A distinguishing feature of all rodent models of MS is the small volume of white matter and damaged tissue compared to human MS brain being typically more than 100-fold smaller. We have developed a rabbit model of demyelination that allows for the generation of demyelinated lesions >10-fold greater than mouse. In preliminary studies, we have established that the large lesion more closely resembles that of human MS lesions than equivalent mouse models. One defining feature is that the rate and extent of OPC migration and colonization of the lesion is much reduced compared to mouse and occurs over a much longer time course. This project will determine if these differences are solely due to the lesion size or if species-specific signaling contributes. We will determine whether promising preclinical therapeutics, clemastine or PI-88, can successfully improve remyelination in the rabbit model. As both drugs have shown success in mouse models and yet have distinct mechanisms of action, the rabbit model of failed recruitment and remyelination may provide additional insight into the best approaches to impr
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110387
Entities
People
- Fraser J Sim
Organizations
- United States Army
- University at Buffalo