Steve Fancy, PhD, DVM
Research description:
Oligodendrocytes are the myelinating cells of the CNS that enable formation of myelin and saltatory nerve conduction. In Multiple Sclerosis (MS), the most common cause of neurological disability in young adults, myelin sheaths are lost through injury or death of mature oligodendrocytes (OL) as a result of autoimmune damage. White matter disorders are also associated with human newborn neurological injuries leading to Cerebral palsy (CP). CP complicates over 3.3/1000 live births in the United States and the incidence of this devastating condition is on the rise due to the increasing rates of survival of very low birth weight premature infants. In these conditions, myelin sheaths can be regenerated by oligodendrocyte progenitors (OLP) that are recruited to lesions and differentiate in a process called remyelination. But evidence suggests that myelin repair often fails in these diseases and this inhibition of remyelination contributes significantly to ongoing neurological dysfunction, axonal loss and disease progression. In order to understand the regulatory factors relevant in human myelin disorders, it is first critical to understand the cellular mechanisms regulating developmental myelination and the remyelination repair process following injury. My lab is a developmental biology lab, with a disease/injury repair orientation, and access to human developmental brain and MS tissue.
Current Projects:
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.
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.
Understanding selective neuronal vulnerability in human cortex in multiple sclerosis
Multiple sclerosis (MS) is characterized by a relapsing–remitting disease course at early stages and a progressive phase marked by neurodegeneration at chronic stages. Whilst several treatments exist for the relapsing phase of disease, one of the greatest unmet needs for patients is a greater understanding of the mechanisms of neurodegeneration in progressive MS, and novel treatments that focus on neuroprotection. Virtually nothing is known about which neurons may be lost in the cortices of MS patients during progression, and why this happens. A recent landmark study made use of single-nucleus RNA sequencing to assess changes in expression in multiple cell lineages in human MS cortical lesions (Nature, 573 (2019) 75-82)(1), and identified for the first time a selective vulnerability of a particular neuronal subtype in MS. It found selective loss of excitatory CUX2 expressing projection neurons in upper-cortical layers underlying meningeal inflammation in MS. These neurons constitute the majority of neurons in human cortical layers 2 and 3. Nothing is known about why these Cux2+ neurons may be more vulnerable than other neuronal cell types in the cortex of MS patients. They have never been identified previously to be more vulnerable in MS or in any animal models of neuroinflammatory disease. It is critical to understand the mechanisms leading to this vulnerability, as loss of these neurons may account for a considerable number of symptoms experienced by MS patients, and understanding the mechanism of their degeneration is required for the development of neuroprotective strategies. Current projects are focused on establishing extrinsic and intrinsic components of these neurons which determine their vulnerability.
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.
Lab members:
Wenlong Xia PhD
Keying Zhu PhD
Trung Huynh
Xiaowen Tang