Mechanical Properties of the Demyelinated Central Nervous System: A Barrier to Remyelination?
Abstract
Remyelination is a key process for CNS repair following trauma or inflammatory damage such as that in multiple sclerosis (MS). There are currently no therapies to promote or enhance myelin repair, particularly in chronic demyelinated MS lesions, which are characterized by poor remyelination. The reasons for this failure remain poorly understood and represent a critical challenge for therapeutics. Cell transplantation involving oligodendrocytes progenitor cells (OPC) derived from autologous induced pluripotent stem cells (iPSC) could be a promising approach, but transplants delivered into areas with already extensive tissue damage often fail. Recent studies from our laboratory demonstrated that mechanical cues delivered by the extracellular environment of the brain (henceforth referred as ECM) are capable of affecting the differentiation of rodent OPC into myelin-forming cells. More importantly, we found that upon demyelination, the stiffness of both rodent and human post-mortem brain changes in a manner that correlates with the regenerative capacity of the lesion. Thus, acute demyelinated lesions (ADL) are softer than uninjured white matter while chronic demyelinated lesions (CDL) are stiffer. Crucially, in preliminary studies using human iPSC lines, we found that when cells are grown in optimal conditions mimicking the stiffness of a healthy ECM the differentiation of OPC is promoted, while if grown in a stiffer ECM the process is hampered. This proposal seeks to understand the causes underlying increased tissue stiffness in CDL and its potential contribution to remyelination failure. To do this, we will engineer novel ECM-like substrates built from two molecules found in the brain and whose expression is known to change following demyelination. The relative ratios and organization of these molecules will be manipulated in a manner that we expect will reproduce the changes in ECM stiffness observed in acute and chronic MS lesions. We will then use these substrates to grow iPSC-derived human glial cells and characterize the changes in gene expression and myelin production induced by different ECM stiffness. Finally, using a preclinical mouse model of chronic demyelination, we will test the idea that human OPC grown in either soft or stiff substrates, acquire a mechanical memory, that either promotes (soft-memory) or inhibits (stiff-memory) their ability to form myelin in vivo. We believed that pharmacological manipulation of this memory can be exploited as an strategy to overcome remyelination failure in chronic MS. In the mid- to long-term, these studies have the potential to impact the field in two major ways: (1) the development of novel strategies to overcome remyelination failure by endogenous adult OPC in chronically demyelinated lesions, and (2) the optimization of methods for reprogramming human iPSC into repair-competent cells and their effective delivery to MS patients. 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
- Dec 28, 2022
- Source ID
- W81XWH2211044
Entities
People
- Carmen Melendez-Vasquez
Organizations
- Research Foundation of The City University of New York
- United States Army