The neurovascular unit in leukodystrophies: towards solving the puzzle

Abstract

The neurovascular unit (NVU) is a highly organized multicellular system localized in the brain, formed by neuronal, glial (astrocytes, oligodendrocytes, and microglia) and vascular (endothelial cells and pericytes) cells. The blood-brain barrier, a complex and dynamic endothelial cell barrier in the brain microvasculature that separates the blood from the brain parenchyma, is a component of the NVU. In a variety of neurological disorders, including Alzheimer's disease, multiple sclerosis, and stroke, dysfunctions of the NVU occurs. There is, however, a lack of knowledge regarding the NVU function in leukodystrophies, which are rare monogenic disorders that primarily affect the white matter. Since leukodystrophies are rare diseases, human brain tissue availability is scarce and representative animal models that significantly recapitulate the disease are difficult to develop. The introduction of human induced pluripotent stem cells (hiPSC) now makes it possible to surpass these limitations while maintaining the ability to work in a biologically relevant human context and safeguarding the genetic background of the patient. This review aims to provide further insights into the NVU functioning in leukodystrophies, with a special focus on iPSC-derived models that can be used to dissect neurovascular pathophysiology in these diseases.

Keywords: Astrocyte; Blood–brain barrier; Endothelium; In vitro models; Induced pluripotent stem cells; Leukodystrophies; Microglia; Neurovascular unit; Pericyte.

Fig. 1

Schematic representation of models to study the NVU in leukodystrophies in humans. The first step of studying leukodystrophies is in a clinical setting, using MRI and next-generation sequencing for initial diagnosis, monitoring disease progression and treatment of patients. Since most leukodystrophies are fatal, post-mortem analysis and post-mortem tissue-derived primary cells, immortalized cell lines, and organotypic slice cultures are valuable tools to distinguish primary cellular processes involved in the pathogenesis. Finally, hiPSC-based models can contribute to investigating the molecular pathways and dynamics at the NVU during disease development and test therapeutic interventions. Together, clinical and basic research can contribute to understanding disease mechanisms in leukodystrophies