Steve Fancy, PhD, DVM
Understanding myelination in human brain development and white matter injury.
Permanent damage to white matter tracts in the CNS is an important component of multiple sclerosis (MS) in adults as well as newborn brain injuries that cause cerebral palsy (CP). In these conditions, a process called remyelination can restore myelin sheaths to demyelinated axons. In this repair process, resting oligodendrocyte progenitor cells (OPCs) in the surrounding normal white matter are activated and migrate into areas of demyelination before undergoing a differentiation step to form mature remyelinating oligodendrocytes. Transcription factors involved in regulating these responses to injury in oligodendrocyte lineage cells remain unclear. We have identified a number of critical transcription factors involved in mediating these OPC recruitment and differentiation processes, required for successful myelin repair.
The human demyelinated lesion as a dysregulated repair environment.
Evidence suggests that myelin repair often fails in MS and CP, and that whilst OPCs are recruited to lesions they are often unable to differentiate into mature myelin-forming oligodendrocytes (OL). This inhibition of OPC differentiation and remyelination failure contributes significantly to ongoing neurological dysfunction, axonal loss and disease progression. It is therefore critical to understand the causes of OPC differentiation block in these debilitating human conditions. We have identified the Wnt pathway as a potent inhibitor of OPC differentiation. Wnt pathway blocks OPC maturation, and must be downregulated to allow any differentiation. We provide evidence that this pathway is pathologically dysregulated in the context of human white matter injury suggesting it as a major candidate for the failed remyelination seen in these diseases, and show that pharmacological inhibition of the pathway can promote the rate of remyelination in vivo.
Development of therapies for human white matter injury.
A significant contributor to progression in Multiple Sclerosis is the failure of the remyelination repair process. Patients taking immunosuppressive therapy or with quiescent disease continue to decline because of this failure of the myelin regenerative response. There are currently no therapies targeting remyelination in MS or in newborn brain injuries that cause cerebral palsy (CP), and this is one of the major unmet needs for patients with these debilitating diseases. We have identified a number of potential candidates as therapeutic targets for promoting remyelination. Pharmacological inhibition of the Wnt pathway (either at the level of the beta catenin degradation complex, or via the cell surface receptor complex for Wnt) accelerates myelin repair in vivo. Additionally, a novel high throughput in vitro screening platform has identified a number of new candidate therapeutics to promote OPC differentiation.
Oligodendrocyte-vascular interactions in the development of the human brain.
During development of the central nervous system (CNS), OPCs arise from the ventricular zone in embryonic brain and spinal cord, in specific domains defined through pattern formation. From these domains, OPCs migrate widely through the CNS to achieve uniform distribution before halting migration and differentiating into oligodendrocytes that myelinate their target axons. Despite decades of work on OPC migration, it has remained unclear how this highly migratory cell type distributes so rapidly around the developing CNS. My lab has provided insight into this developmental migration recently by demonstrating that OPCs use and require vasculature as a physical scaffold for their motility (Science 351, 379 (2016)). Additionally, we find that OPCs utilize a similar single cell perivascular migration for recruitment into lesions following demyelination. We find that this migration can be defective in human Multiple Sclerosis (MS), and that OPCs form perivascular clusters around blood vessels in lesions. We show that this aberrant oligodendroglial-vascular interaction is detrimental to the health of the underlying vessel, disrupting the blood brain barrier, and may act as a contributor to pathology in human MS. We have also uncovered several other aspects of oligodendroglial-vascular interaction in development and disease, including the angiogenic capacity of OPCs during postnatal development. We have also shown that CNS fibrosis is derived from activation of CNS fibroblasts that reside around large parenchymal vessels, and that this fibrosis limits OPC entry into neuroinflammatory lesions.
Resilience genes in cerebellum development and medulloblastoma survival.
Medulloblastoma is the most common childhood brain cancer in humans, and can arise from granule cell progenitors in the developing cerebellum. We have recently identified a pair of co-resilience genes that in combination are required for the development of these granule cell progenitors in the developing cerebellum. In the absence of these genes, these cells are specified and migrate from the rhombic lip, but fail to survive during a vulnerability period as they proliferate in the external granule layer at late embryonic times in the mouse. Loss of these resilience genes in the SmoM2 murine model of medulloblastoma also leads to a significantly reduced growth of the tumor. This will have significant therapeutic potential in the future for this pediatric cancer.