Induction of Oligodendrocyte Progenitor Cell Differentiation by Blocking Store-Operated Oscillatory Calcium Release
Abstract
The focus area of this application is Central Nervous System Regenerative Potential in Demyelinating Conditions. This application utilizes a series of mechanistic studies to investigate the calcium-dependent pathways, which act as obstacles to myelin repair in human and mouse models. The hypothesis and approach are novel and innovative, utilizing state-of-the-art human primary cells, viral approaches, and transgenic animal models. The brain contains a population of neural stem/progenitor cells that largely 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. When oligodendrocytes are lost or damaged in demyelinating diseases, such as multiple sclerosis (MS), this 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 MS, 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. Previous studies by our group and others have identified that muscarinic receptors expressed on the surface of OPCs signal in an inhibitory fashion to prevent efficient oligodendrocyte formation and delay remyelination. While antimuscarinic drugs have begun being tested in the clinic in early phase 1/2 trials, an effective therapy that blocks this receptor is likely to be accompanied by significant adverse effects on patient cognition. As such, we have sought to better understand the mechanisms that muscarinic receptors act upon and thereby identify novel points of intervention that may offer advantages for improving remyelination in the progressive MS. In preliminary studies, we have established that specific waves of calcium release occur during inhibitory muscarinic signaling and that these waves are capable of blocking OPC differentiation in human cells. We have also observed that the calcium release occurs in the nucleus of the cell and is positioned to directly alter gene expression by binding to specific proteins. By blocking these calcium waves, we have found that OPCs are able to overcome these obstacles and differentiate into oligodendrocytes even in the presence of inhibitory signals. The mechanistic studies described in this proposal will characterize the nature of the calcium signals in the nucleus and define which pathways contribute to blocked differentiation. We will also use genetic and pharmacological approaches in vivo to address whether selectively altering calcium release in OPCs could alter myelin repair in a mouse model of demyelination. The successful completion of these studies will provide a mechanistic understanding of the role of these pathways in human cells and provide a clear path forward for the development of these strategies into more translational approaches. As such, the basic nature of these studies is unlikely to yield a short-term clinical benefit, but, instead, we expect that this project will drive the field of OPC biology forward and open up new avenues for future regenerative therapies and intervention.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210709
Entities
People
- Fraser J Sim
Organizations
- United States Army
- University at Buffalo