Neuro-Lymphatic // Science

Until recently, the CNS has been considered devoid of a proper lymphatic system. However, recent studies have revealed the existence of a specific system, which involves the glymphatic system (i.e., the astrocyte-mediated interexchange between the Cerebral Spinal Fluid and the Interstitial fluid), and the collector lymphatic vessels present in the meninges surrounding the CNS.

It has been demonstrated in physiological conditions this system plays a role in the clearance of the macromolecules accumulating in the brain parenchyma. However, its involvement and role in the development of brain disorders has not yet been characterized.

Scope

Our research goal is to study the functionality of the CNS lymphatic system both in physiological and pathological conditions. We are studying its function in the clearance of brain waste products, in the neuro-immunological interactions, and in the neuronal circuitry functionality.

Our specific research interests are

  • Imaging of the functionality of the CNS lymphatic system in healthy and pathological conditions
  • Role of the CNS lymphatic system in brain immune surveillance
  • Interaction between the CNS lymphatic system and the neuronal network activity
  • Involvement of the CNS lymphatic system in the pathophysiology of neurodegenerative disorders

Methodological approaches

In order to investigate the structure and function of the CNS lymphatic system, our Group uses clinical-relevant murine models of brain injury as well as genetic and pharmacological methodologies. Our models include traumatic brain injury models, acute seizure models and epilepsy models (mainly TLE). In order to study the functionality of meningeal lymphatic system, we take advantage of K14-VEGFR3 tg mice (lacking dermal and meningeal lymphatic vessels), and of virus mediated gene transfer methods, to specifically manipulate the expression of meningeal lymphatic vessels in adult mice.

We use a multidisciplinary approach that involves in vivo imaging techniques (MRI and multi-photon microscopy), electroencephalography, behavioral tests, FACS analysis, and molecular biology (e.g. immunohistochemistry and western blot).

In collaboration with Kuopio University hospital (KYS), we have, also, access to human tissue samples from TBI and meningioma patients.

Translational relevance

During the last decades, scientists have recognized that the causes of several neurological disorders should be searched “outside” the brain, such as in the neurovascular interaction. However, the complete pathophysiological mechanisms of neurodegenerative diseases remain elusive. We hypothesize that the CNS lymphatic system is another important player in the control of brain function, which goes beyond the pure brain homeostasis, determining also the neuro-immune interaction, and ultimately influencing the functions of the neuronal circuitries.

Understanding how macromolecules are cleared from the brain and how these mechanisms determine the neuro-immune interaction, represent intriguing questions in both physiological and pathological conditions.

In the development of post-traumatic neurodegenerative disorders (such as chronic traumatic encephalopathy, post-traumatic epilepsy, and different types of dementia), brain edema, improper protein accumulation (e.g., tau and amyloid beta), neuroinflammation and lymphocyte infiltration, represent important causes of secondary brain injury.

Although no specific data are available about the role of the CNS lymphatic system in post-TBI disorders, we can presume that the glymphatic system and the meningeal lymphatic vessels are involved in the regulation of one or all of the TBI secondary injury factors. The study of the functionality of the CNS lymphatic system, therefore, represent an innovative and important approach to better understand the mechanisms of neuronal damage and to find novel therapeutic targets.

Collaborations

We believe that no excellent science can be done alone without a continuous open and productive discussion.

In building a strong collaboration network both internal at UEF, and external (which includes e.g. collaboration with University of Helsinki and Ludwig-Maximillian University of Munchen), we pursue our objective of a multidisciplinary and innovative research approach to better understand the role of the CNS lymphatic system in the complex interactions within the brain, and between the CNS and immune system.

Funding

The Academy of Finland (#309479)

Jane and Aatos Erkko Foundation (Academy Prof. Asla Pitkänen)