In demyelinating diseases such as multiple sclerosis (MS) and Periventricular Leukomalacia associated with Cerebral Palsy (CP), myelin sheaths are lost through injury or death of oligodendrocytes (OL). Remyelination by oligodendrocyte precursor cells (OPCs) is considered crucial to recovery, but myelin repair often fails contributing significantly to ongoing neurological dysfunction, axonal loss and disease progression. There are currently no therapies to promote remyelination, and one of the greatest unmet needs is gaining a greater understanding of the obstacles to successful myelin repair. Remyelination can be divided into two critical stages: Firstly (1) recruitment of migrating OPCs into areas of demyelination from surrounding normal appearing white matter followed by (2) their differentiation into mature OL within the lesion. We have recently identified that OPCs migrate during their developmental dispersal around the CNS using vasculature as a physical scaffold for motility (Science 351, 379 (2016)). This requires movement along vessels, but also subsequent detachment from vasculature after migration to allow OPC differentiation. The mechanism of migration of OPCs into remyelinating lesions, critical for successful myelin repair, remains largely unclear. This grant will (1) identify for the first time how OPCs are recruited into remyelinating lesions utilizing vasculature as a physical scaffold for motility. It will (2) demonstrate that failure of OPCs to detach from vasculature appropriately is a pathological finding in human white matter injury. It will identify this inability to detach not only as a mechanism preventing their proper distribution into lesions but also as an obstacle for subsequent OPC differentiation. (3) It will show that OPCs remaining inappropriately attached to vessels interfere with astrocyte-vascular coupling and integrity of the blood brain barrier that may contribute further to lesion pathology.
/ PUBLIC HEALTH RELEVANCE Evidence suggests that in both Multiple Sclerosis and Cerebral Palsy there is disease progression, neurological dysfunction, and axonal loss due to a failed myelin regeneration response, and that myelin repair can fail because of failed oligodendrocyte precursor cell (OPC) migration/recruitment into lesions or from their failed differentiation into mature oligodendrocytes (OL). Here we will identify how OPCs migrate into remyelinating lesions using blood vessels as a physical scaffold, demonstrate that this can become dysregulated in human white matter injury, and that failure of OPCs to properly detach from vasculature is a mechanism preventing OPC recruitment into lesions, a mechanism for their blocked differentiation, and also may interfere with astrocyte-vascular coupling and integrity of the blood brain barrier contributing further to pathology. The work in this grant will significantly contribute to our understanding of the obstacles to myelin repair in these debilitating human diseases.
| Daynac, Mathieu; Chouchane, Malek; Collins, Hannah Y et al. (2018) Lgl1 controls NG2 endocytic pathway to regulate oligodendrocyte differentiation and asymmetric cell division and gliomagenesis. Nat Commun 9:2862 |
